746 Cancer cachexia associated Fc receptor expression on leukocytes as potential mechanism of checkpoint inhibitor resistance in patients and in murine cancer models

Background

Cancer cachexia is a multifactorial syndrome characterized by irreversible loss of skeletal muscle and adipose tissue resulting from increased catabolism and metabolic activity.¹Patients with cachexia are generally resistant to immune checkpoint inhibitor (ICI) therapy while also displaying elevated monoclonal antibody (mAb) catabolic clearance (CL), and this increased CL serves as a prognostic indicator of overall survival, independent of dose received.^{2 3} Increased ICI CL is also replicated in the murine Lewis lung carcinoma (LLC) model of cancer cachexia but is absent in the non-cachectic MC38 colon adenocarcinoma model.⁴ Elevated ICI CL is independent of mAb variable region and target binding, suggesting an important role for the Fc constant region and Fc domain binding to Fc receptors (FcRs). FcRs (FcRn + FcgRs) also play a critical role in both the pharmacokinetics (PK) and efficacy of ICI therapy.^{5 6} We sought to understand cachexia-associated changes in leukocyte FcR expression as it pertains to ICI PK and efficacy.

Methods

Mass cytometry time-of-flight (CyTOF) was used to assess circulating immune cells and FcR expression in peripheral blood mononuclear cells (PBMCs) from cancer patients and in mouse splenocytes. Healthy C57BL/6 mice and mice with LLC or MC38 tumors were used to investigate the effect of cachexia on FcR expression. PBMCs were obtained from patients receiving either pembrolizumab, nivolumab, or combination nivolumab and ipilimumab for the treatment of non-small cell lung cancer or renal cell carcinoma. Cachexia in these patients was assessed using L3 CT image analysis of skeletal muscle index (SMI).⁷

Results

Many cachexia associated changes in leukocyte FcR expression were observed. Both FcgRI⁸ and FcgRIIb^{9 10} play a role in ICI PK and efficacy, and both illustrate a general inverse trend between expression and cachexia severity with less expression in cachectic patients and animals. We also observed trends between FcR expression and ICI CL that could potentially explain observed differences in CL in clinical patients. Cachectic mice displayed decreased circulating CD8+ T cells, which was also supported in humans in which patients displaying low SMI had lower levels of CD8+ T cells at the time of ICI therapy initiation.

Conclusions

Many studies have highlighted the importance of Fc and FcR interaction on the therapeutic activity and PK of ICIs, however no studies have characterized expressional changes in FcRs as a function of disease state. Here, we highlight how disease state can mediate FcR expressional changes in patterns that can potentially explain altered ICI PK and efficacy.

References

Baracos VE, et al. Cancer-associated cachexia. Nat Rev Dis Primers, 2018;4:17105. Shiroyama T, et al. Impact of sarcopenia in patients with advanced non-small cell lung cancer treated with PD-1 inhibitors: A preliminary retrospective study. Sci Rep, 2019;9(1):2447. Turner DC, et al. Pembrolizumab Exposure-Response Assessments Challenged by Association of Cancer Cachexia and Catabolic Clearance. Clin Cancer Res, 2018;24(23):5841–5849. Castillo AMM, et al. Murine cancer cachexia models replicate elevated catabolic pembrolizumab clearance in humans. JCSM Rapid Commun, 2021;4(2):232–244. Challa DK, et al. Neonatal Fc receptor expression in macrophages is indispensable for IgG homeostasis. MAbs, 2019;11(5):848–860. Dahan R, et al. FcgammaRs Modulate the Anti-tumor Activity of Antibodies Targeting the PD-1/PD-L1 Axis. Cancer Cell, 2015;28(3):285–95. Mourtzakis M, et al. A practical and precise approach to quantification of body composition in cancer patients using computed tomography images acquired during routine care. Appl Physiol Nutr Metab, 2008;33(5):997–1006. Zhang T, et al. The binding of an anti-PD-1 antibody to FcgammaRIota has a profound impact on its biological functions. Cancer Immunol Immunother, 2018;67(7):1079–1090. Arlauckas SP, et al. In vivo imaging reveals a tumor-associated macrophage-mediated resistance pathway in anti-PD-1 therapy. Sci Transl Med, 2017;9(389). Oldham RJ, et al. FcgammaRII (CD32) modulates antibody clearance in NOD SCID mice leading to impaired antibody-mediated tumor cell deletion. J Immunother Cancer, 2020;8(1).

Ethics Approval

Animal experiments were conducted according to protocols approved by The Ohio State University Institutional Animal Care and Use Committee (protocol #2017A00000117). Human studies were approved by The Ohio State University Cancer Institutional Review Board, approval #2020C0048.