Infections and Immunotherapy in Lung Cancer: A Bad Relationship?

Infectious diseases represent a relevant issue in lung cancer patients. Bacterial and viral infections might influence the patients’ prognosis, both directly affecting the immune system and indirectly impairing the outcome of anticancer treatments, mainly immunotherapy. In this analysis, we aimed to review the current evidence in order to clarify the complex correlation between infections and lung cancer. In detail, we mainly explored the potential impact on immunotherapy outcome/safety of (1) bacterial infections, with a detailed focus on antibiotics; and (2) viral infections, discriminating among (a) human immune-deficiency virus (HIV), (b) hepatitis B/C virus (HBV-HCV), and (c) Sars-Cov-2. A series of studies suggested the prognostic impact of antibiotic therapy administration, timing, and exposure ratio in patients treated with immune checkpoint inhibitors, probably through an antibiotic-related microbiota dysbiosis. Although cancer patients with HIV, HBV, and HCV were usually excluded from clinical trials evaluating immunotherapy, some retrospective and prospective trials performed in these patient subgroups reported similar results compared to those described in not-infected patients, with a favorable safety profile. Moreover, patients with thoracic cancers are particularly at risk of COVID-19 severe outcomes and mortality. Few reports speculated about the prognostic implications of anticancer therapy, including immunotherapy, in lung cancer patients with concomitant Sars-Cov-2 infection, showing, to date, inconsistent results. The correlation between infectious diseases and immunotherapy remains to be further explored and clarified in the context of dedicated trials. In clinical practice, the accurate and prompt multidisciplinary management of lung cancer patients with infections should be encouraged in order to select the best treatment options for these patients, avoiding unexpected toxicities, while maintaining the anticancer effect.     

Immunoprofiling: An Encouraging Method for Predictive Factors Examination in Lung Cancer Patients Treated with Immunotherapy

The efficiency of immunotherapy using monoclonal antibodies that inhibit immune checkpoints has been proven in many clinical studies and well documented by numerous registration approaches. To date, PD-L1 expression on tumor and immune cells, tumor mutation burden (TMB), and microsatellite instability (MSI) are the only validated predictive factors used for the qualification of cancer patients for immunotherapy. However, they are not the ideal predictive factors. No response to immunotherapy could be observed in patients with high PD-L1 expression, TMB, or MSI. On the other hand, the effectiveness of this treatment method also may occur in patients without PD-L1 expression or with low TMB and with microsatellite stability. When considering the best predictive factor, we should remember that the effectiveness of immunotherapy relies on an overly complex process depending on many factors. To specifically stimulate lymphocytes, not only should their activity in the tumor microenvironment be unlocked, but above all, they should recognize tumor antigens. The proper functioning of the anticancer immune system requires the proper interaction of many elements of the specific and non-specific responses. For these reasons, a multi-parameter analysis of the immune system at its different activity levels is considered a very future-oriented predictive marker. Such complex immunological analysis is performed using modern molecular biology techniques. Based on the gene expression studies, we can determine the content of individual immune cells within the tumor, its stroma, and beyond. This includes all cell types from active memory cytotoxic T cells, M1 macrophages, to exhausted T cells, regulatory T cells, and M2 macrophages. In this article, we summarize the possibilities of using an immune system analysis to predict immunotherapy efficacy in cancer patients. Moreover, we present the advantages and disadvantages of immunoprofiling as well as a proposed future direction for this new method of immune system analysis in cancer patients who receive immunotherapy.     

The Utilization of the Immune System in Lung Cancer Treatment: Beyond Chemotherapy

Lung cancer is ranked first worldwide as one of the main cancers in terms of prevalence and mortality rate. The development of effective treatment strategies against lung cancer is therefore of paramount importance. Traditionally, chemotherapy was employed in the treatment of various cancers. However, the non-specific nature of the actions of chemotherapeutic drugs and the potential for tumors to develop resistance to these drugs may render chemotherapy a less favorable option for cancer treatment. Immunotherapy provides an alternative strategy for this purpose. It involves the utilization of the immune system and the immune effector cells to elicit an immune response to the tumors, thereby eliminating them. Strategies include the administration of pro-inflammatory cytokines for immune stimulation, the removal of immunological checkpoints using monoclonal antibodies, and the use of cancer vaccines to enhance immunity against tumors. This article summarizes the above strategies, highlights the reasons why immunotherapy is superior to chemotherapy for the purpose of tumor removal, and reviews the recent clinical studies comparing the clinical outcomes of patients undergoing immunotherapy and chemotherapy. The article also describes advances in immunotherapeutic strategies for the treatment of lung cancer.     

EGFR-Mutated Non-Small Cell Lung Cancer and Resistance to Immunotherapy: Role of the Tumor Microenvironment

Lung cancer is a leading cause of cancer-related deaths worldwide. About 10–30% of patients with non-small cell lung cancer (NSCLC) harbor mutations of the EGFR gene. The Tumor Microenvironment (TME) of patients with NSCLC harboring EGFR mutations displays peculiar characteristics and may modulate the antitumor immune response. EGFR activation increases PD-L1 expression in tumor cells, inducing T cell apoptosis and immune escape. EGFR-Tyrosine Kinase Inhibitors (TKIs) strengthen MHC class I and II antigen presentation in response to IFN-γ, boost CD8+ T-cells levels and DCs, eliminate FOXP3+ Tregs, inhibit macrophage polarization into the M2 phenotype, and decrease PD-L1 expression in cancer cells. Thus, targeted therapy blocks specific signaling pathways, whereas immunotherapy stimulates the immune system to attack tumor cells evading immune surveillance. A combination of TKIs and immunotherapy may have suboptimal synergistic effects. However, data are controversial because activated EGFR signaling allows NSCLC cells to use multiple strategies to create an immunosuppressive TME, including recruitment of Tumor-Associated Macrophages and Tregs and the production of inhibitory cytokines and metabolites. Therefore, these mechanisms should be characterized and targeted by a combined pharmacological approach that also concerns disease stage, cancer-related inflammation with related systemic symptoms, and the general status of the patients to overcome the single-drug resistance development.     

The Role of Gut Microbiota in Overcoming Resistance to Checkpoint Inhibitors in Cancer Patients: Mechanisms and Challenges

The introduction of immune checkpoint inhibitors has constituted a major revolution in the treatment of patients with cancer. In contrast with the traditional cytotoxic therapies that directly kill tumor cells, this treatment modality enhances the ability of the host’s immune system to recognize and target cancerous cells. While immune checkpoint inhibitors have been effective across multiple cancer types, overcoming resistance remains a key area of ongoing research. The gut microbiota and its role in cancer immunosurveillance have recently become a major field of study. Gut microbiota has been shown to have direct and systemic effects on cancer pathogenesis and hosts anti-tumor immune response. Many studies have also shown that the host microbiota profile plays an essential role in the response to immunotherapy, especially immune checkpoint inhibitors. As such, modulating this microbial environment has offered a potential path to overcome the resistance to immune checkpoint inhibitors. In this review, we will talk about the role of microbiota in cancer pathogenesis and immune-system activity. We will also discuss preclinical and clinical studies that have increased our understanding about the roles and the mechanisms through which microbiota influences the response to treatment with immune checkpoint inhibitors.     

The Immunotherapy for Colorectal Cancer,Lung Cancer and Pancreatic Cancer

Immunotherapy is a novel anti-cancer method which employs a different mechanism to conventional treatment. It has become a significant strategy because it provides a better or an alternative option for cancer patients. Recently, immunotherapy has been increasingly approved for the treatment of cancer; however, it has various limitations; for instance, it is only suitable for specific patients, the response rate is still low in most cases, etc. Colorectal cancer, lung cancer and pancreatic cancer are known as three major death-causing cancers in most countries. In this review, we discuss immunotherapeutic treatment for these three cancers, and consider the option, prospects and limitations of immunotherapy. The development of immunotherapy should focus on the discovery of biomarkers to screen suitable patients, new targets on tumors, neoadjuvant immunotherapy and the combination of immunotherapy with conventional therapeutic methods. We can expect that immunotherapy potentially will develop as one of the best therapies for patients with advanced cancer or poor responses to traditional methods.     

Future Prospects of Immunotherapy in Non-Small-Cell Lung Cancer Patients: Is There Hope in Other Immune Checkpoints Targeting Molecules?

Currently, one of the leading treatments for non-small-cell lung cancer is immunotherapy involving immune checkpoint inhibitors. These monoclonal antibodies restore the anti-tumour immune response altered by negative immune checkpoint interactions. The most commonly used immunotherapeutics in monotherapy are anti-PD-1 and anti-PD-L1 antibodies. The effectiveness of both groups of antibodies has been proven in many clinical trials, which have translated into positive immunotherapeutic registrations for cancer patients worldwide. These antibodies are generally well tolerated, and certain patients achieve durable responses. However, given the resistance of some patients to this form of therapy, along with its other drawbacks, such as adverse events, alternatives are constantly being sought. Specifically, new drugs targeting already known molecules are being tested, and new potential targets are being explored. The aim of this paper is to provide an overview of the latest developments in this area.     

What Are the Biomarkers for Immunotherapy in SCLC?

Small-cell lung cancer (SCLC) is an aggressive malignancy that exhibits a rapid doubling time, a high growth fraction, and the early development of widespread metastases. The addition of immune checkpoint inhibitors to first-line chemotherapy represents the first significant improvement of systemic therapy in several decades. However, in contrast to its effects on non-SCLC, the advantageous effects of immunotherapy addition are modest in SCLC. In particular, only a small number of SCLC patients benefit from immune checkpoint inhibitors. Additionally, biomarkers selection is lacking for SCLC, with clinical trials largely focusing on unselected populations. Here, we review the data concerning the major biomarkers for immunotherapy, namely, programmed death ligand 1 expression and tumour mutational burden. Furthermore, we explore other potential biomarkers, including the role of the immune microenvironment in SCLC, the role of genetic alterations, and the potential links between neurological paraneoplastic syndromes, serum anti-neuronal nuclear antibodies, and outcomes in SCLC patients treated with immunotherapy.     

Role of the Microbiota in Lung Cancer: Insights on Prevention and Treatment

The microbiota is increasingly recognized as a critical player in cancer onset and progression and response to cancer chemotherapy treatment. In recent years, several preclinical and clinical studies have evidenced the involvement of microbiota in lung cancer, one of the world’s deadliest cancers. However, the mechanisms by which the microbiota can impact this type of cancer and patient survival and response to treatments remain poorly investigated. In this review, the peculiarities of the gut and lung microbial ecosystems have been highlighted, and recent findings illustrating the possible mechanisms underlying the microbiota–lung cancer interaction and the host immune response have been discussed. In addition, the mucosal immune system has been identified as a crucial communication frame to ease interactive dynamics between the immune system and the microbiota. Finally, the use of specific next-generation intestinal probiotic strains in counteracting airway diseases has been evaluated. We believe that restoring homeostasis and the balance of bacterial microflora should become part of the routine of integrated cancer interventions, using probiotics, prebiotics, and postbiotics, and promoting a healthy diet and lifestyle.     

Monitoring Immunotherapy With Optical Molecular Imaging

Immunotherapy is an effective way to mobilize the body‘s own immune system to confront tumor cells. However, the efficacy of immunotherapy is affected by tumor heterogeneity, and the low therapeutic response to immunotherapy may lead to negative outcomes, which reinforces the urgency for early benefit predictors. Evaluating the infiltration of immune cells in solid tumors and metabolism changes of tumors provide potential response targets for monitoring immune response. Non-invasive imaging identifying prognostic biomarkers can select the beneficiaries of targeted immunotherapy from non-responses. Quantitative biomarkers may eventually improve the cancer management, help customize individual treatment plans and predict the treatment outcomes. In this review, we summarize the non-invasive optical molecular imaging methods for monitoring immunotherapy. With the combination of imaging and immunotherapy, the prediction of immunotherapy response may promote the development of precision medicine.     

TMB in NSCLC: A Broken Dream?

Although immune checkpoint inhibitors have changed the treatment paradigm of a variety of cancers, including non-small-cell lung cancer, not all patients respond to immunotherapy in the same way. Predictive biomarkers for patient selection are thus needed. Tumor mutation burden (TMB), defined as the total number of somatic/acquired mutations per coding area of a tumor genome (Mut/Mb), has emerged as a potential predictive biomarker of response to immune checkpoint inhibitors. We found that the limited use of TMB in clinical practice is due to the difficulty in its detection and compounded by several different biological, methodological and economic issues. The incorporation of both TMB and PD-L1 expression or other biomarkers into multivariable predictive models could result in greater predictive power.     

Gender differences in insulin-induced free fatty acid suppression: Studies in an african american population

This study of African Americans (AA) was designed to investigate gender differences in insulin-induced free fatty acid (FFA) suppression. Sixty AA (34 women, mean age 34±7.6 years, and 26 men, mean age 30±2.9 years) participated. All subjects had an oral glucose tolerance test (OGTT). Nineteen women and 18 men also underwent a euglycemic hyperinsulinemic clamp (IC) study. Plasma insulin and FFA concentrations were obtained during both test at 0, 60, and 120 min. While there was no gender difference in body mass index (P=0.21), women had greater percent body fat (P<0.001) calculated by the Siri formula. There was no gender difference in fasting FFA levels, but during the OGTT, women compared to men had significantly greater FFA suppression. Both nonobese and obese women suppressed FFA concentration by 88%, and nonobese and obese men suppressed, FFA concentration by 80 and 66%, respectively. This gender difference in FFA suppression was significant (P=0.001) and independent of obesity and insulin concentration. During the IC studies, there were no gender or obesity differences in FFA suppression, with women and men suppressing FFA levels by 87–89% (P=0.7). Fasting insulin concentrations were higher in obese vs. nonobese (P=0.03), but fasting FFA concentrations were not different (P=0.15). For nonobese and obese, females, fasting FFA levels were 0.55±0.24 and 0.44±0.26 mEq/L, respectively, and for nonobese and obese males, 0.45±0.2 and 0.35±0.18 mEq/L, respectively. In women, development of obesity may be enhanced by greater sensitivity to insulin-induced FFA suppression as measured during an OGTT. To detect gender differences in FFA metabolism, the OGTT is superior to the IC. The lack of elevation in fasting FFA levels in obese AA women and men has not been reported in other racial groups and may indicate a greater adipocyte sensitivity to insulin in AA.     

Self‐Assembled Nano‐Immunostimulant for Synergistic Immune Activation

Immunotherapy has become one of the most promising therapies for the treatment of diseases. Synthetic immunostimulants and nanomaterial immunostimulant systems are indispensable for the activation of the immune system in cancer immunotherapy. Herein, a strategy for preparing self‐assembled nano‐immunostimulants (SANIs) for synergistic immune activation is reported. Three immunostimulants self‐assemble into nanoparticles through electrostatic interactions. SANIs showed strong synergistic immunostimulation in macrophages. SANIs could also induce a strong antitumor immune response to inhibit tumor growth in mice and act as an efficient adjuvant of antitumor vaccines. Therefore, SANIs may be generally applied in cancer immunotherapy. This novel SANI strategy provides a new way for the development of both immunostimulants and ‐suppressants.     

TNFα and Immune Checkpoint Inhibition: Friend or Foe for Lung Cancer?

Tumor necrosis factor-alpha (TNFα) can bind two distinct receptors (TNFR1/2). The transmembrane form (tmTNFα) preferentially binds to TNFR2. Upon tmTNFα cleavage by the TNF-alpha-converting enzyme (TACE), its soluble (sTNFα) form is released with higher affinity for TNFR1. This assortment empowers TNFα with a plethora of opposing roles in the processes of tumor cell survival (and apoptosis) and anti-tumor immune stimulation (and suppression), in addition to angiogenesis and metastases. Its functions and biomarker potential to predict cancer progression and response to immunotherapy are reviewed here, with a focus on lung cancer. By mining existing sequencing data, we further demonstrate that the expression levels of TNF and TACE are significantly decreased in lung adenocarcinoma patients, while the TNFR1/TNFR2 balance are increased. We conclude that the biomarker potential of TNFα alone will most likely not provide conclusive findings, but that TACE could have a key role along with the delicate balance of sTNFα/tmTNFα as well as TNFR1/TNFR2, hence stressing the importance of more research into the potential of rationalized treatments that combine TNFα pathway modulators with immunotherapy for lung cancer patients.     

Dendritic Cells and Cancer Immunotherapy: The Adjuvant Effect

Dendritic cells (DCs) are immune specialized cells playing a critical role in promoting immune response against antigens, and may represent important targets for therapeutic interventions in cancer. DCs can be stimulated ex vivo with pro-inflammatory molecules and loaded with tumor-specific antigen(s). Protocols describing the specific details of DCs vaccination manufacturing vary widely, but regardless of the employed protocol, the DCs vaccination safety and its ability to induce antitumor responses is clearly established. Many years of studies have focused on the ability of DCs to provide overall survival benefits at least for a selection of cancer patients. Lessons learned from early trials lead to the hypothesis that, to improve the efficacy of DCs-based immunotherapy, this should be combined with other treatments. Thus, the vaccine’s ultimate role may lie in the combinatorial approaches of DCs-based immunotherapy with chemotherapy and radiotherapy, more than in monotherapy. In this review, we address some key questions regarding the integration of DCs vaccination with multimodality therapy approaches for cancer treatment paradigms.     

Immunology and Immunotherapeutic Approaches for Advanced Renal Cell Carcinoma: A Comprehensive Review

Renal cell carcinoma (RCC) is a malignant tumor associated with various tumor microenvironments (TMEs). The immune system is activated by the development of cancer and drives T cell anti-tumor response. CD8 T cells are known to improve clinical outcomes and sensitivity to immunotherapy, and play a crucial role against tumors. In contrast, tumor-associated macrophages (TAMs) suppress immunity against malignancy and lead to tumor progression. TAMs are promoted from damaged TMEs and mount proinflammatory responses to pathogens. Initial immunotherapy consists of interferon-α and interleukin-2. However, response to such therapy is unclear in most patients, and it is associated with high levels of toxicity. Immune checkpoint inhibitors (ICIs), which up-regulate immune responses by blocking the programed cell death protein 1 (PD-1) receptor, the ligand of PD-1, or cytotoxic T-lymphocyte-associated protein 4 T cells, have led to a new era of immunotherapy. Furthermore, combination strategies with ICIs have proven effective through several randomized controlled trials. We expect the next generation of immunotherapy to lead to better outcomes based on ongoing trials and inspire new therapeutic strategies.     

Targeting DNA Damage Response and Immune Checkpoint for Anticancer Therapy

Deficiency in DNA damage response (DDR) genes leads to impaired DNA repair functions that will induce genomic instability and facilitate cancer development. However, alterations of DDR genes can serve as biomarkers for the selection of suitable patients to receive specific therapeutics, such as immune checkpoint blockade (ICB) therapy. In addition, certain altered DDR genes can be ideal therapeutic targets through adapting the mechanism of synthetic lethality. Recent studies indicate that targeting DDR can improve cancer immunotherapy by modulating the immune response mediated by cGAS-STING-interferon signaling. Investigations of the interplay of DDR-targeting and ICB therapies provide more effective treatment options for cancer patients. This review introduces the mechanisms of DDR and discusses their crucial roles in cancer therapy based on the concepts of synthetic lethality and ICB. The contemporary clinical trials of DDR-targeting and ICB therapies in breast, colorectal, and pancreatic cancers are included.     

The Role of Somatic Mutations on the Immune Response of the Tumor Microenvironment in Prostate Cancer

Immunotherapy has improved patient survival in many types of cancer, but for prostate cancer, initial results with immunotherapy have been disappointing. Prostate cancer is considered an immunologically excluded or cold tumor, unable to generate an effective T-cell response against cancer cells. However, a small but significant percentage of patients do respond to immunotherapy, suggesting that some specific molecular subtypes of this tumor may have a better response to checkpoint inhibitors. Recent findings suggest that, in addition to their function as cancer genes, somatic mutations of PTEN, TP53, RB1, CDK12, and DNA repair, or specific activation of regulatory pathways, such as ETS or MYC, may also facilitate immune evasion of the host response against cancer. This review presents an update of recent discoveries about the role that the common somatic mutations can play in changing the tumor microenvironment and immune response against prostate cancer. We describe how detailed molecular genetic analyses of the tumor microenvironment of prostate cancer using mouse models and human tumors are providing new insights into the cell types and pathways mediating immune responses. These analyses are helping researchers to design drug combinations that are more likely to target the molecular and immunological pathways that underlie treatment failure.     

Hepatocellular Carcinoma Immunotherapy and the Potential Influence of Gut Microbiome

Disruptions in the human gut microbiome have been associated with a cycle of hepatocyte injury and regeneration characteristic of chronic liver disease. Evidence suggests that the gut microbiota can promote the development of hepatocellular carcinoma through the persistence of this inflammation by inducing genetic and epigenetic changes leading to cancer. As the gut microbiome is known for its effect on host metabolism and immune response, it comes as no surprise that the gut microbiome may have a role in the response to therapeutic strategies such as immunotherapy and chemotherapy for liver cancer. Gut microbiota may influence the efficacy of immunotherapy by regulating the responses to immune checkpoint inhibitors in patients with hepatocellular carcinoma. Here, we review the mechanisms by which gut microbiota influences hepatic carcinogenesis, the immune checkpoint inhibitors currently being used to treat hepatocellular carcinoma, as well as summarize the current findings to support the potential critical role of gut microbiome in hepatocellular carcinoma (HCC) immunotherapy.     

Rho-Kinase as a Target for Cancer Therapy and Its Immunotherapeutic Potential

Cancer immunotherapy is fast rising as a prominent new pillar of cancer treatment, harnessing the immune system to fight against numerous types of cancer. Rho-kinase (ROCK) pathway is involved in diverse cellular activities, and is therefore the target of interest in various diseases at the cellular level including cancer. Indeed, ROCK is well-known for its involvement in the tumor cell and tumor microenvironment, especially in its ability to enhance tumor cell progression, migration, metastasis, and extracellular matrix remodeling. Importantly, ROCK is also considered to be a novel and effective modulator of immune cells, although further studies are needed. In this review article, we describe the various activities of ROCK and its potential to be utilized in cancer treatment, particularly in cancer immunotherapy, by shining a light on its activities in the immune system.