Eric Berno

Background: Lung cancer was the most commonly diagnosed cancer and leading cause of cancer-related death worldwide in 2022, with non-small cell lung cancer (NSCLC) making up 85% of those cases.¹ There are many treatment options for NSCLC depending on location and biomarker status, including  surgery, chemotherapies, targeted therapies, and immunotherapy. ¹ One of the most common immunotherapy mechanisms involves the PD1/PD-L1 interaction, in which antibodies to PD1 or PD-L1 are used to prevent cancer cells from inhibiting CD8 T cells capable of killing the cancer cells. ^{2, 3} Although these immunotherapies (ICIs) have shown efficacy in some patients, over 60% of treatment-naive NSCLC patients eventually develop resistance to these ICIs due to a variety of mechanisms, including immunosuppression mechanisms carried out by M2 macrophages involved in the tumor microenvironment (TME). ^{3, 4} Multiple drug resistance mechanisms carried out by these M2 macrophages are mediated by their FcyR, thus providing a potential therapeutic target to enhance immunotherapy efficacy.

Objective: In this narrative review, I explored the mechanisms of ICI drug resistance mediated by the FcyR of M2 macrophages in NSCLC.

Search Methods: A PubMed database search was conducted from 2017-2024 using the following keywords: “NSCLC”, “Immunotherapy”, “Drug Resistance”, “Macrophages”, and “Tislelizumab”.

Results: The TAM-associated FcyR mediates ICI resistance through formation of a cross-link between TAMs and Effector T cells bound by ICI. ⁵ This inhibits the effector T cell functions in a variety of ways, including stimulating TAM antibody-dependent cellular phagocytosis of Effector T cells and stimulating anti-inflammatory cytokine production. ⁵ This cross-linking to the FcyR was shown to be mediated by the IgG4_S228p heavy chain of ICI, which is a portion of the antibody used in the most common ICI. ⁵ When ICI with and without the IgG4_S228p heavy chain was tested in mice tumor models, the ICI without the IgG4_S228p heavy chain showed significant tumor growth inhibition as compared to the ICI with the IgG4_S228p heavy chain. ⁵ The FcyR also facilitates ICI resistance via mediating transfer of the ICI antibody from effector T cells to M2 macrophages, thus allowing cancer cells to interact with effector T cells using their PD-L1, introducing anergy in the effector T cells. ⁶ When an FcyR blocking agent was introduced before ICI therapy using in vitro experiments, the transfer of the ICI Ab from effector T cells to M2 macrophages was severely diminished, providing some evidence that the FcyR is involved in the transfer. ⁶ This was then tested in mice tumor models, and this method showed substantially enhanced tumor regression.^.6

Conclusion: As discussed above, the FcyR of M2 macrophages can play a significant role in drug resistance to ICI therapy by mediating cross-linking between M2 macrophages to effector T cells and by facilitating transfer of the ICI Ab from effector T cells to M2 macrophages. The applications of this research are currently being studied via the drug Tislelizumab, which is an ICI designed to minimize binding to the FcyR.

Works Cited:

1. Hendriks LEL, Remon J, Faivre-Finn C, Garassino MC, Heymach JV, Kerr KM, Tan DSW, Veronesi G, Reck M. Non-small-cell lung cancer. Nat Rev Dis Primers. 2024 Sep 26;10(1):71. doi: 10.1038/s41572-024-00551-9. Erratum in: Nat Rev Dis Primers. 2025 Jan 7;11(1):3. doi: 10.1038/s41572-025-00592-8. PMID: 39327441.
2. Lahiri A, Maji A, Potdar PD, Singh N, Parikh P, Bisht B, Mukherjee A, Paul MK. Lung cancer immunotherapy: progress, pitfalls, and promises. Mol Cancer. 2023 Feb 21;22(1):40. doi: 10.1186/s12943-023-01740-y. PMID: 36810079; PMCID: PMC9942077.
3. Nowicki TS, Hu-Lieskovan S, Ribas A. Mechanisms of Resistance to PD-1 and PD-L1 Blockade. Cancer J. 2018 Jan/Feb;24(1):47-53. doi: 10.1097/PPO.0000000000000303. PMID: 29360728; PMCID: PMC5785093.
4. Huang S, Chung JY, Li C, Wu Y, Qiao G, To KF, Tang PM. Cellular dynamics of tumor microenvironment driving immunotherapy resistance in non-small-cell lung carcinoma. Cancer Lett. 2024 Nov 1;604:217272. doi: 10.1016/j.canlet.2024.217272. Epub 2024 Sep 24. Erratum in: Cancer Lett. 2024 Dec 27:217425. doi: 10.1016/j.canlet.2024.217425. PMID: 39326553.
5. Zhang T, Song X, Xu L, Ma J, Zhang Y, Gong W, Zhang Y, Zhou X, Wang Z, Wang Y, Shi Y, Bai H, Liu N, Yang X, Cui X, Cao Y, Liu Q, Song J, Li Y, Tang Z, Guo M, Wang L, Li K. The binding of an anti-PD-1 antibody to FcγRΙ has a profound impact on its biological functions. Cancer Immunol Immunother. 2018 Jul;67(7):1079-1090. doi: 10.1007/s00262-018-2160-x. Epub 2018 Apr 23. PMID: 29687231; PMCID: PMC6006217.
6. Arlauckas SP, Garris CS, Kohler RH, et al. In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci Transl Med. 2017;9(389):eaal3604. doi:10.1126/scitranslmed.aal3604