Combination of chemotherapy (CT) with PD-1 blockade is a front-line treatment for lung cancer. Our aim was to explore CT effects on CD8 T cells that proliferate in response to concomitant PD-1 blockade.
To reproduce the exhausted immune landscape of cancer, we used a well-established murine model of chronic lymphocytic choriomeningitis virus (LCMV) infection. At day 45 post-infection, mice were assigned to 4 treatment groups (untreated, CT, aPD-L1, combo). The CT regimen consisted of cisplatin (2.5 mg/kg) and pemetrexed (300 mg/kg). CT and aPDL1 were given every 3 days for 2 weeks. This regimen was tested also in the syngeneic CT26 tumor model and T cell phenotyping was performed after 4 doses (day 20 post-tumor implantation).
In the LCMV model, LCMV-sp CD8 T cells in lymphoid and non-lymphoid tissues were lower in the combo vs aPD-L1. Proliferation of LCMV-sp CD8 T cell was higher in combo than in chemo and untreated, but lower than in aPD-L1. Frequency of stem-like LCMV-sp CD8 was higher in chemo group vs the others, with no differences in absolute numbers. The effector subsets, both the transitory and terminally differentiated, were more vulnerable, resulting in decreased IFN-g production and viral control in the combo compared to the aPD-L1 group. In the tumor model, CT and/or aPD-L1 delayed tumor growth. Compared to the untreated group, tumor infiltrating Ag-sp and PD-1+ CD8 T cells were significantly higher not only in the aPD-L1 and combo groups, but also in the chemo group. Though non-significant, frequency of proliferating Ag-sp CD8 T cells was lower in combo vs aPD-L1 group. Frequency of stem-like cells was low, without significant differences across groups.
Chemotherapy attenuates the proliferation of effector cells mediated by concomitant PD-1 blockade. The preservation of the stem-like subset, that provide the proliferative burst needed for an effector T cell response, suggests that chemotherapy toxicity on CD8 T cells is likely transient and reversible after discontinuation of chemotherapy.
The authors.
Emory University, Emory Vaccine Center.
S. Novello: Financial Interests, Personal, Invited Speaker: AstraZeneca, MSD, Eli Lilly, Novartis, Beigene, Amgen; Financial Interests, Personal, Advisory Board: BI, BMS, Pfizer, Takeda, Roche, Sanofi, Amgen; Financial Interests, Institutional, Invited Speaker, IIT: MSD, BI; Non-Financial Interests, Personal, Leadership Role, president of this european advocacy: WALCE. G. Scagliotti: Financial Interests, Personal, Other, Honoraria/Consultant: AstraZeneca, Eli Lilly, MSD, Pfizer, Roche, J&J, Takeda, BeiGene, Bayer. S.S. Ramalingam: Financial Interests, Institutional, Other, Consultant: Amgen, BMS, Merck, AstraZeneca, Takeda, Eisai, Daiichi Sankyo, GSK; Financial Interests, Personal, Other, Editor in Chief, Cancer journal: American Cancer Society; Financial Interests, Personal, Research Grant: Merck, AstraZeneca, Advaxis, BMS, Amgen, Takeda, Genmab, GSK. R. Ahmed: Other, Personal, Other, patent: Anti-PD-1 monoclonal antibodies; Other, Personal and Institutional, Funding, research fundings: Merck. All other authors have declared no conflicts of interest.