Front Oncol 9: 1384

Lung Cancer Heterogeneity in Modulation of Th17/IL17A Responses

Pro-Tumor Effect of IL17A

Chronic inflammation is one of the hallmarks of malignant transformations (3). Induction of IL17A to various inflammatory conditions promotes the recruitment of innate immune cells such as neutrophils, and macrophages (12). Cigarette smoking which is associated with over 80% of all lung cancers, recruits Th17 cells in the lungs (13, 14), and has been associated with poor survival in NSCLC patients (15). Serum IL17A level is positively linked to vascular endothelial growth factor (VEGF) concentration in NSCLC patients, suggesting IL17A may promote angiogenesis in the tumor (16). Further, patients with high serum IL17A concentrations demonstrated a shorter overall survival rate compared with those with low levels (17). High IL17A levels also correlated with increased lymph node invasion, and distant metastases in NSCLC (17). Several meta-analyses have shown that high IL17A expression prognosticated poorer survival outcome or late stage diagnosis in NSCLC patients (18–20). Th17 cell infiltration also positively correlated to poor prognostic outcome in several other types of cancer, including colon, gastric, and liver. In contrast, Th17 cell infiltration in ovarian cancer has been shown to associate with better survival (21), while in nasopharyngeal cancer patients there was no significant association between tumor-infiltrating Th17 cells and survival, indicating a specific role for Th17 cells based on the specific tumor (22).

In addition to Th17 cells and association with tumor survival, chemokines and their receptors related to trafficking of this T cell subset have also been examined in NSCLC. For instance, high expression of CCR6, a chemokine receptor expressed by Th17 cells (23), was associated with shorter disease-free survival in NSCLC patients. Similarly, CCL20, the only chemokine known to interact with CCR6 (24), was elevated in the tumor compared to tumor-free adjacent lung tissue (25). Together, these findings suggest that the CCL20/CCR6 axis might facilitate infiltration of Th17 cell in NSCLC and promote tumor progression (25).

In addition to IL17A, Th17 cells can also secrete other cytokines, including IL-22 (26). Although elevated IL-22 expression has been detected in the primary lung tumor, serum, and malignant pleural effusion in patients (27, 28), its expression did not correlate with prognostic outcome in smokers with NSCLC (27). Further, IL-23, another cytokine that is secreted by myeloid cells and can polarize naive CD4^{T cells to Th17 cells (}29, 30), was found to be elevated in the serum of lung cancer patients compared with healthy controls (31). Similarly, however, there is no known correlation between IL-23 expression and NSCLC prognosis to date.

Anti-tumor Effect of IL17A

Multiple lines of evidence suggest that IL17A/Th17 may play a pro-tumorigenic role as an increased number of Th17 cells are found in human colorectal (32), gastric (33), hepatocellular (34), and lung cancers (35). However, despite the aforementioned-association studies, recent evidence also suggests the possibility for an immuno-protective role of Th17 cells in tumors. Different subsets of TILs in NSCLC can produce IL17A, such as natural killer, natural killer T cells, and γδT cells (36) but CD4^{stem cell-like memory T cells showed the highest expression of this cytokine (}37). Since Th17 cells could transdifferentiate into interferon-gamma (IFN-γ)-secreting Th1 cells (38, 39), increased Th17 cells infiltrate into the tumor may promote tumor regression. In support of this concept, induction of Th17 cells to IFN-γ-secreting Th1 cells and differentiation into a durable stem memory phenotype enhances long-term anti-tumor responses (37, 40), and this feature has been applied in adoptive T cell transfer therapy in a murine preclinical model (41).

Targeting Th17 or IL17A pathways as a treatment for cancer has not yet been reported in clinical trials; however, two recent reports suggest their important role in anti-tumor activity. In one case, humanized monoclonal anti-IL17 treatment of psoriatic lesions in a patient with colon cancer was associated with cancer relapse after initial successful therapy with anti-programmed cell death protein 1 (PD-1) (42), though it is not clear whether this patient would have relapsed without the depletion of IL17A. Another case showed that anti-PD-1 treatment in patients with melanoma increased Th17 cell numbers in responders compared to non-responders (43). Although the role of Th17 cells in checkpoint blockade treatments remains unknown, these clinical reports highlight a potential anti-tumor effect of Th17 cells in immune-targeted therapy.

Prospective

The summation of evidence reveals there are opposing roles for Th17 cells in different genetic drivers of cancer, though there are still some essential remaining knowledge gaps. It appears that different cancers respond distinctly to similar immune contextures. Mouse models thus far have been limited in the genetic mutations and investigation of their corresponding immune responses. Furthermore, clinical observations need to be extended to clinical studies. Future human NSCLC studies are needed to assess the immune infiltrates with different oncogenic foci. Further, how different cancers respond to, or whether tumors are reinforced or inhibited by various immune contextures, should be investigated using new sequencing techniques, and through immunogenomics of tumor samples (84–86). Genetic sequencing, mass spectrometry, and other high throughput methods can provide genetic mutation of tumor cells and the corresponding immune setting in its microenvironment (85). Therapeutically, immunogenomics is an approach to identify neo-antigens for vaccination and T cell therapy (85, 86). Determining how genetic alterations specifically affect the immune system will open up more opportunities for immunotherapy and personalized medicine. For an exploration of immunotherapy, it may be beneficial to further investigate the potential of Th17 cells in CAR-T cell therapy. Given the findings in murine models, knowing the underlying genetics of a patient's tumor may inform whether enhancing or dampening a Th17 response would improve outcomes for patients in personalized medicine.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

^{Department of Medicine, Baylor College of Medicine, Houston, TX, United States}

^{Center for Translational Research on Inflammatory Diseases (CTRID), Michael E. DeBakey Department of Veterans Affairs, Houston, TX, United States}

^{Department of Pathology and Immunology, Baylor College of Medicine, Houston, TX, United States}

^{Biology of Inflammation Center, Baylor College of Medicine, Houston, TX, United States}

Edited by: Humam Kadara, University of Texas MD Anderson Cancer Center, United States

Reviewed by: Seon Hee Chang, University of Texas MD Anderson Cancer Center, United States; Nejat K. Egilmez, University of Louisville, United States

*Correspondence: Farrah Kheradmand ude.mcb@kharraf

This article was submitted to Cancer Immunity and Immunotherapy, a section of the journal Frontiers in Oncology

†These authors have contributed equally to this work

Edited by: Humam Kadara, University of Texas MD Anderson Cancer Center, United States

Reviewed by: Seon Hee Chang, University of Texas MD Anderson Cancer Center, United States; Nejat K. Egilmez, University of Louisville, United States

Received 2019 Sep 9; Accepted 2019 Nov 22.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

Abstract

The interplay between tumors and their immune microenvironment is critical for cancer development and progression. The discovery of tumor heterogeneity has provided a window into a complex interplay between tumors, their secreted products, and host immune responses at the cellular and molecular levels. Tumor heterogeneity can also act as a driving force in promoting treatment resistance and correlates with distinct tumor-mediated acquired immune responses. A prevailing question is how genetic aberrations in solid tumors can shape the immune landscape, resulting in pro-tumor or anti-tumor activities. Here we review evidence for clinical and pathophysiological mechanisms that underlie different types of non-small cell lung cancer (NSCLC) and provide new insights for future immunomodulatory-based therapies. Some of the more common driver mutations in NSCLC heterogeneity includes the opposing immune responses in oncogenic mutations in K-ras vs. non-K-ras models and their pro-inflammatory cytokines such as interleukin (IL)17A. We will discuss possible molecular and metabolic mechanisms that may govern the opposing immune responses observed in distinct genetic models of NSCLCs. A deeper understanding of how tumor heterogeneity modulates immune response can improve current therapeutic strategies and provide precise treatment to individual lung cancer patients.

Keywords: tumor heterogeneity, lung cancer, immune landscape, tumor microenvironment, immunotherapy, Th17, IL17A

Abstract

Acknowledgments

We acknowledge the contributions of Dr. Ran You, that aided the efforts of the authors.

Acknowledgments

Footnotes

Funding. This work was supported by NIH grants R01ES029442-01 and R01 AI135803-01, VA Merit grant CX000104 to FK, and DC NIOSH, Southwest Center for Occupational and Environmental Health, Pilot Projects Research Training Award-T42 and Baylor College of Medicine Comprehensive Cancer Training Program-CPRIT RP160283 to C-YC, and the National Institute of General Medical Sciences of the NIH under award number T32GM088129 to DA.

Footnotes

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