Induction of a CD8 T cell intrinsic DNA damage and repair response isassociated with clinical response to PD-1 blockade in uterine canc
Muroyama Y. et al. (BioRxiv) DOI: 10.1101/2022.04.16.488552
DNA Damage Response
Authors identified a cohort of patients with MSI-H, MMRd or hypermutated uterine cancers being treated with immune checkpoint inhibitor against PD-1,nivolumab. These patients usually have high tumor mutation burden (due to MMR defects) as well as large infiltration of expanding T-cells and should respond well to immune checkpoint blockade(ICB).
A subset of patients within the cohort did not respond to therapy, even though they had high tumor mutation burden (TMB)and proliferating T-cells that were similar to clinical responders in their ability to divide and proliferate, leading to the hypothesis that there are T-cell intrinsic differences in response to proliferation and genotoxic stress that could be causing differential outcomes in response to ICB
To interrogate this, they developed a high dimensional, single-cell platform using flow cytometry to profile 7 different memory T-cell states as well as DNA Damage Response (DDR)pathways(using pATM,γH2AX, PARP1 andMSH2)activated upon induction of proliferative stress, UV and irradiation
Using patient samples, they saw that pATM was differentially upregulated in proliferating cells(Ki67+ cells)within clinical responders, particularly in Tex cells that are the target for anti PD1 therapy
They created ATM null CD8 T-cells using CRISPR and performed RNA seq to identify genes that are differentially upregulated in response to proliferative stress using gene set enrichment in ATMKO vs WT CD8 T cells. Using these genes that were specifically activated, they created an ATM-Responder Gene Signature(ARGS).
Authors then looked at cohorts of Uterine Corpus Endometrial Carcinoma, Colorectal adenocarcinoma, and Skin Cutaneous Melanoma in The Cancer Genome Atlas. They found that patients who have a higher expression of ARGS genes are associated with better overall survival
Overall, the authors identified patterns of DNA Damage Response (DDR)defects in different CD8 subsets that make them more likely to respond to PD-1 blockade and showed that the ability to induce ATM activation (pATM) inCD8 T-cells during PD-1 blockade is more robust in clinical responders
Small sample size
Data limited to peripheral T-cells
Did not look at other cells in the immune compartment
What is the novelty of the preprint for the field specific?
Showed that patients treated with chemotherapy/radiation may have increased genome instability and altered T-cell function based on changes in DDR that were previously unexplored.
Uncovered a previously unknown effect of DDR that is intrinsic to CD8 T-cells and is higher in responders across multiple cancer types.
DDRd have mostly been implicated in tumour cell biology but this paper shows its importance in the functioning of T-cells, especially upon rapid proliferation and replicative stress which is induced after ICB.
Developed a platform to assay changes in DDR as well as T-cell differentiation and activation.
How does the result of the preprint matter for general immunologists and/or patients?
Reiterates that having high TMB and infiltration of CD8 T-cells is not enough for response to therapy and proposes alternative biomarkers/ pathways that can be used for better prediction of response to therapy.
Shows the importance of T-cell intrinsic functionality in response to therapy-pATM may be used as a biomarker to help select patients that will respond better to PD1 blockade.
Reviewed by Prerna Suri as part of the cross-institutional journal club of the Immunology Institute of the Icahn School of Medicine, Mount Sinai, and the Kennedy Institute of Rheumatology, University of Oxford.