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AACR-AstraZeneca Lung Cancer Fellow Shows How Blocking an Arginine Methyltransferase Can Overcome Immunotherapy Resistance

T-cell exhaustion can dampen the response to immune checkpoint blockade (ICB). These exhausted T cells have previously been shown to undergo epigenetic changes;  reversing these changes can potentially restore T-cell activity. An AACR-AstraZeneca Lung Cancer Fellow, Sushil Kumar, PhD, demonstrated how inhibition of an epigenetic regulator, arginine methyltransferase CARM1, resulted in not only enhanced anti-tumor activity of T cells but also increased susceptibility of tumor cells to T cell-mediated killing. 

Sushil Kumar, PhD

Dr. Kumar received an AACR-AstraZeneca Lung Cancer Research Fellowship in 2018, bolstering his efforts to identify epigenetic regulators of tumor infiltrating CD8 T cells in lung cancer that suppress T cell function.  

In this recent paper in Cancer Discovery, he reports that the Carm1 gene was the top hit in an in vivo CRISPR/Cas9 screen designed to uncover negative regulators of anti-tumor immunity. Knocking out Carm1 in T cells made the T cells more effective, at least in part due to increased expression of granzyme B and the cytokines IL-2, IFN gamma, and TNF alpha. Tumor-infiltrating Carm1-KO T cells appeared to be more persistent – continuing to express the CD69 activation marker at early (16 days) and late (24 days) time points after T cell transfer in mice. Only a small percentage of the Carm1-KO cells expressed markers of exhausted T cells: PD-1 and Tim-3 inhibitory receptors or CD39. 

Carm1 is also expressed in high levels in a diverse range of human cancer cell lines, portending Carm1’s role in tumor biology. Although knocking out Carm1 in breast cancer and melanoma cells did not affect proliferation in vitro, these Carm1-deficient cells’ ability to survive and grow in immunocompetent mice was significantly hindered. Analyzing tumors formed by these Carm1-KO cancer cells showed a significant increase in the number of infiltrating CD8 T cells, along with a decrease in the percentage of CD8 T cells that expressed PD-1 and Tim-3.  Downregulation of Carm1 either through genetic knockout or pretreatment with a small-molecule inhibitor (EZM2302) made cancer cells more sensitive to T-cell mediated cytotoxicity. 

Dr. Kumar’s group further showed that treatment with a Carm1 inhibitor sensitized mice with ICB-resistant tumors (B16F10 melanoma and 4T1 breast cancer) to anti-CTLA4. Combining the Carm1 inhibitor with an immune checkpoint blockade antibody (anti-CTLA-4 or anti-PD-1) resulted not only in increase in tumor infiltration of CD8 T cells but also of NK and dendritic cells. The plausible role of Carm1 in influencing response to ICB was further supported by findings in patient tumor samples. Tumors from ICB responders contained significantly lower levels of CARM1 and MED12 (a CARM1 substrate) mRNA than non-responders.

These results point to the therapeutic potential of Carm1 inhibition, especially in ICB-resistant tumors. Given that Carm1 downregulation let to increased vulnerability of cancer cells to T-cell-mediated cytotoxicity, Carm1 inhibitors also hold promise in combination with other T-cell dependent therapies, such as neoantigen-based cancer vaccines and CAR T cell strategies.