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Review
. 2022 Jul;10(7):e004863.
doi: 10.1136/jitc-2022-004863.

Addressing CPI resistance in NSCLC: targeting TAM receptors to modulate the tumor microenvironment and future prospects

Solange Peters  1 , Luis Paz-Ares  2 , Roy S Herbst  3 , Martin Reck  4
Affiliations
Review

Addressing CPI resistance in NSCLC: targeting TAM receptors to modulate the tumor microenvironment and future prospects

Solange Peters et al. J Immunother Cancer. 2022 Jul.

Abstract

Lung cancer remains a leading cause of cancer death worldwide, with non-small-cell lung cancer (NSCLC) accounting for the majority of cases. Immune checkpoint inhibitors (CPIs), including those targeting programmed cell death protein-1 and its ligand (PD-1/PD-L1), have revolutionized the treatment landscape for various cancers. Notably, PD-1/PD-L1 inhibitor-based regimens now form the standard first-line therapy for metastatic NSCLC, substantially improving patients' overall survival. Despite the progress made using CPI-based therapies in advanced NSCLC, most patients experience disease progression after an initial response due to resistance. Given the currently limited therapeutic options available for second-line and beyond settings in NSCLC, new treatment approaches are needed to improve long-term survival in these patients. Thus, CPI resistance is an emerging concept in cancer treatment and an active area of clinical research.Among the key mechanisms of CPI resistance is the immunosuppressive tumor microenvironment (TME). Effective CPI therapy is based on shifting immune responses against cancer cells, therefore, manipulating the immunosuppressive TME comprises an important strategy to combat CPI resistance. Several aspects of the TME can contribute to treatment resistance in NSCLC, including through the activation of Tyro3, Axl, MerTK (TAM) receptors which are essential pleiotropic regulators of immune homeostasis. Their roles include negatively modulating the immune response, therefore ectopic expression of TAM receptors in the context of cancer can contribute to the immunosuppressive, protumorigenic TME. Furthermore, TAM receptors represent important candidates to simultaneously target both tumor cells and immune cells in the TME. Clinical development of TAM receptor inhibitors (TAM RIs) is increasingly focused on their ability to rescue the antitumor immune response, thereby shifting the immunosuppressive TME to an immunostimulatory TME. There is a strong biological rationale for combining TAM RIs with a CPI to overcome resistance and improve long-term clinical responses in NSCLC. Combinatorial clinical trials of TAM RIs with CPIs are underway with encouraging preliminary results. This review outlines the key mechanisms of CPI resistance, including the role of the immunosuppressive TME, and discusses the rationale for targeting TAM receptors as a novel, promising therapeutic strategy to overcome CPI resistance in NSCLC.

Keywords: immunotherapy; review; tumor microenvironment.

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Conflict of interest statement

Competing interests: SP has participated in consulting and/or advisory boards for AbbVie, Amgen, AstraZeneca, Bayer, Beigene, Biocartis, Boehringer Ingelheim, Bristol Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, ecancer, Eli Lilly, Elsevier, Foundation Medicine, Illumina, Incyte, Janssen, Merck Sharp and Dohme, Merck Serono, Merrimack, Novartis, Pharma Mar, Phosplatin Therapeutics, Pfizer, Regeneron, RMEI, Roche/Genentech, Sanofi, Seattle Genetics and Takeda. SP has spoken at organized public events for AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Illumina, Merck Sharp and Dohme, Novartis, Pfizer, Roche/Genentech, Sanofi, and Takeda outside the submitted work. LP-A has participated as a speaker, consultant or in advisory boards for Amgen, AstraZeneca, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Eli Lilly, Ipsen, Merck, Merck Sharp & Dohme, Mirati Therapeutics, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, Sysmex, and Takeda outside the submitted work. MR has reported honoraria and consultancy for Amgen, AstraZeneca, Bristol Myers Squibb, Boehringer Ingelheim, Lilly, Merck, Mirati Therapeutics, Inc., Merck Sharp & Dohme, Novartis, Pfizer, Sanofi Aventis, and Roche outside the submitted work. RSH reports personal fees from Abbvie Pharmaceuticals, ARMO Biosciences, Bolt Biotherapeutics, Bristol-Myers Squibb, Cybrexa Therapeutics, eFFECTOR Therapeutics, Inc., EMD Serono, Genmab, Halozyme Therapeutics, Heat Biologics, I-Mab Biopharma, Infinity Pharmaceuticals, Loxo Oncology, Mirati Therapeutics, Nektar, Neon Therapeutics, NextCure, Novartis, Oncternal Therapeutics, Pfizer, Sanofi, Seattle Genetics, Shire PLC, Spectrum Pharmaceuticals, STCube Pharmaceuticals, Inc, Symphogen, Takeda, Tesaro, Tocagen, WindMIL Therapeutics, Xencor, Inc., Candel Therapeutics, Inc., Ribbon Therapeutics, Bayer HealthCare Pharmaceuticals, Inc., Checkpoint Therapeutics, Foundation Medicine, Inc., Gilead, Johnson and Johnson, Refactor Health, Inc., DynamiCure Biotechnology, and Ventana Medical Systems, Inc., grants and personal fees from AstraZeneca, Eli Lilly and Company, Genentech/Roche, and Merck and Company, and other from Immunocore and Junshi Pharmaceuticals.

Figures

Figure 1
Figure 1
CPI resistance in NSCLC: the role of the tumor microenvironment (TME). CPI, checkpoint inhibitor; MDSCs, myeloid-derived suppressor cells; NSCLC, non-small-cell lung cancer; TIGIT, tyrosine-based inhibition motif domain.
Figure 2
Figure 2
Key immunomodulatory pathways within the TME targeted by TAM-targeted RTKs (including TAM TKI sitravatinib). RTK, receptor tyrosine kinase; TAM, Tyro3, Axl, MerTK; TKI, tyrosine kinase inhibitor; TME, tumor microenvironment.
See this image and copyright information in PMC

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