ccr-23-1316_supplementary_figure_s1_suppfs1.pptx (316.9 kB)

Supplementary Figure S1 from Platinum-Based Chemotherapy Attenuates the Effector Response of CD8 T Cells to Concomitant PD-1 Blockade

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posted on 2024-05-01, 07:21 authored by Annapaola Mariniello, Tahseen H. Nasti, Daniel Y. Chang, Masao Hashimoto, Sakshi Malik, Daniel T. McManus, Judong Lee, Donald J. McGuire, Maria A. Cardenas, Pablo Umana, Valeria Nicolini, Rustom Antia, Ananya Saha, Zachary Buchwald, Hayden Kissick, Ehsan Ghorani, Silvia Novello, Dario Sangiolo, Giorgio V. Scagliotti, Suresh S. Ramalingam, Rafi Ahmed

(A) Number of total lymphocytes, CD8 and CD4 T cells in the spleen across the treatment groups. (B-C) Frequency of PD-1+ and LCMV-specific CD8 T cells in the spleen and in the lung. Data are pooled from 2-3 experiments of 4-5 mice per group. For statistical analysis, the one-way ANOVA test was used; total numbers were Log10 transformed. Bars represent mean and SEM. *p<0.05; ** p<0.01; *** p<0.001; **** p<0.0001.

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

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National Institutes of Health (NIH)

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ARTICLE ABSTRACT

Combination of chemotherapy with programmed cell death 1 (PD-1) blockade is a front-line treatment for lung cancer. However, it remains unknown whether and how chemotherapy affects the response of exhausted CD8 T cells to PD-1 blockade. We used the well-established mouse model of T-cell exhaustion with chronic lymphocytic choriomeningitis virus (LCMV) infection to assess the effect of chemotherapy (cisplatin+pemetrexed) on T-cell response to PD-1 blockade, in the absence of the impact of chemotherapy on antigen release and presentation observed in tumor models. When concomitantly administered with PD-1 blockade, chemotherapy affected the differentiation path of LCMV-specific CD8 T cells from stem-like to transitory effector cells, thereby reducing their expansion and production of IFNγ. After combination treatment, these restrained effector responses resulted in impaired viral control, compared with PD-1 blockade alone. The sequential combination strategy, where PD-1 blockade followed chemotherapy, proved to be superior to the concomitant combination, preserving the proliferative response of exhausted CD8 T cells to PD-1 blockade. Our findings suggest that the stem-like CD8 T cells themselves are relatively unaffected by chemotherapy partly because they are quiescent and maintained by slow self-renewal at the steady state. However, upon the proliferative burst mediated by PD-1 blockade, the accelerated differentiation and self-renewal of stem-like cells may be curbed by concomitant chemotherapy, ultimately resulting in impaired overall CD8 T-cell effector functions. In a translational context, we provide a proof-of-concept to consider optimizing the timing of chemo-immunotherapy strategies for improved CD8 T-cell functions.See related commentary by Vignali and Luke, p. 1705