Therapeutic Implications of Tumor Microenvironment in Lung Cancer: Focus on Immune Checkpoint Blockade.

Carlo Genova,Simona Coco,Guido Ferlazzo,Gilberto Filaci,Paolo Pronzato,Michela Croce,Rosaria Gangemi,Chiara Dellepiane,Paolo Carrega,Sara Sommariva

doi:10.3389/fimmu.2021.799455

Abstract

In the last decade, the treatment of non-small cell lung cancer (NSCLC) has been revolutionized by the introduction of immune checkpoint inhibitors (ICI) directed against programmed death protein 1 (PD-1) and its ligand (PD-L1), or cytotoxic T lymphocyte antigen 4 (CTLA-4). In spite of these improvements, some patients do not achieve any benefit from ICI, and inevitably develop resistance to therapy over time. Tumor microenvironment (TME) might influence response to immunotherapy due to its prominent role in the multiple interactions between neoplastic cells and the immune system. Studies investigating lung cancer from the perspective of TME pointed out a complex scenario where tumor angiogenesis, soluble factors, immune suppressive/regulatory elements and cells composing TME itself participate to tumor growth. In this review, we point out the current state of knowledge involving the relationship between tumor cells and the components of TME in NSCLC as well as their interactions with immunotherapy providing an update on novel predictors of benefit from currently employed ICI or new therapeutic targets of investigational agents. In first place, increasing evidence suggests that TME might represent a promising biomarker of sensitivity to ICI, based on the presence of immune-modulating cells, such as Treg, myeloid derived suppressor cells, and tumor associated macrophages, which are known to induce an immunosuppressive environment, poorly responsive to ICI. Consequently, multiple clinical studies have been designed to influence TME towards a pro-immunogenic state and subsequently improve the activity of ICI. Currently, the mostly employed approach relies on the association of “classic” ICI targeting PD-1/PD-L1 and novel agents directed on molecules, such as LAG-3 and TIM-3. To date, some trials have already shown promising results, while a multitude of prospective studies are ongoing, and their results might significantly influence the future approach to cancer immunotherapy.

Highlights

In the last decades, a remarkable shift in the clinical management of non-small cell lung cancer (NSCLC) patients has been driven by the introduction of immune checkpoint inhibitors (ICI) targeting the axis involving programmed death protein 1 (PD1) and its ligand (PD-L1)
ICI are the standard of care, either as monotherapy or in combination, for advanced non-oncogene-addicted Non-small Cell Lung Cancer (NSCLC) patients
A portion of patients do not benefit from these treatments and it is increasingly clear that reverting T or NK cytotoxic cell dysfunctional state with anti-programmed Cell Death-1 Receptor (PD-1)/PD-L1 and/ or anti-cytotoxic Tlymphocyte-associated protein 4 (CTLA-4) may not be enough and needs to be improved

Summary

Introduction

A remarkable shift in the clinical management of non-small cell lung cancer (NSCLC) patients has been driven by the introduction of immune checkpoint inhibitors (ICI) targeting the axis involving programmed death protein 1 (PD1) and its ligand (PD-L1). The introduction of these agents brought to unprecedented durability in the responses compared to chemotherapy. The combination of the anti-PD-1 agent nivolumab and anti-CTLA-4 agent ipilimumab associated with two cycles of platinum-based chemotherapy achieved improved outcomes compared to firstline chemotherapy in the randomized, phase III CheckMate 9LA trial Even in this case, the experimental combination achieved superior results irrespective of PD-L1 expression [7]

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Conclusion