Checkpoint inhibitors play a critical role in immunotherapy. Unfortunately, they don’t work all the time. For reasons that have been largely unknown, some patients respond to checkpoint inhibitor therapies, while others do not.

Scientists at the University of Colorado (CU) Cancer Center published a study (“Histone-deacetylase inhibition sensitizes PD1 blockade-resistant B-cell lymphomas”) in Cancer Immunology Research that, they say, offers some insight and possibly an inroad into this problem: In mouse models of B-cell lymphoma, adding a histone deacetylase (HDAC) inhibitor sensitized cancers to anti-PD1 therapy.

“I think this combination is definitely worth trying,” said Jing Wang, MD, PhD, investigator at CU Cancer Center and associate professor in the CU School of Medicine department of immunology and microbiology.

The reason this combination works is a bit complex. However, it may help to explain not only why some patients fail to respond to anti-PD1 immunotherapy, but also why HDAC inhibitors, which have seemed so promising in the lab, have been largely unsuccessful with patients.

The reason has to do with another set of proteins, i.e., the major histocompatibility complex (MHC). In fact, MHC describes a few classes of proteins. Basically, MHC proteins grab little bits of proteins from inside a cell and present them on the cell surface for inspection by our T cells. And when T cells recognize a dangerous antigen sitting on an MHC platter, they attack that cell, unless the T cell is deactivated by the PD1/PD-L1 interaction.

If a cancer cell has no MHC proteins, it doesn’t matter if immunotherapy blocks the PD1/PD-L1 interaction. Without MHC, the cancer cell presents no antigens and so the immune system sees no danger.

“PD1-blockade is effective in a subset of B-cell lymphoma patients (e.g., classical-Hodgkin lymphomas); however, most patients do not respond to anti-PD1 therapy. To study PD1-resistance, we used an isoform-selective histone-deacetylase-inhibitor (HDACi) (OKI-179), and a mouse mature B-cell lymphoma, G1XP lymphoma, immunosuppressive features of which resemble those of human B-cell lymphomas, including downregulation of major histocompatibility complex (MHC) class I and II, exhaustion of CD8+ and CD4+ tumor infiltrating lymphocytes (TILs), and PD1-blockade resistance,” write the investigators in their research article.

“Using two lymphoma models, we show that treatment of B-cell lymphomas refractory to PD1-blockade with both OKI-179 and anti-PD1 inhibited growth; furthermore, sensitivity to single or combined treatment required tumor-derived MHC class I, and positively correlated with MHC class II expression level. We conclude that OKI-179 sensitizes lymphomas to PD1-blockade by enhancing tumor immunogenicity. Additionally, we found that different HDACi exhibited distinct effects on tumors and T cells, yet the same HDACi could differentially affect HLA expression on different human B-cell lymphomas.

“Our study highlights the immunological effects of HDACi on antitumor responses and suggests that optimal treatment efficacy requires personalized design and rational combination based on prognostic biomarkers (e.g., MHCs) and the individual profiles of HDACi.”

“T cells recognize antigens in the context of MHC. Without MHC, you can’t present an antigen. And about 60% of diffuse large B cell lymphomas downregulate MHC,” explained Wang.

This is one side of the story: Anti-PD1 immunotherapies may not work in cancers that downregulate MHC. Here is the other side: It appears that the class of drugs known as HDAC inhibitors upregulate MHC. Specifically, the study showed that the experimental HDAC inhibitor OKI-179 (provided by OnKure Therapeutics and currently in a Phase I clinical trial at CU Cancer Center) was like a switch: Without OKI-179, the group’s models of B-cell lymphoma resisted anti-PD1 therapy; with OKI-179 added to anti-PD1 therapy, cancer cells were killed.

“We treated our mouse model of B-cell lymphoma with this HDAC inhibitor. The inhibitor alone had some effect, but when we combined it with anti-PD1 it worked a lot better. Dual inhibition—both HDAC and PD1—achieved a better effect,” Wang continued.

Finally, the study may help to explain why previous HDAC inhibitors have struggled. Remember, there are two systems at work—the PD1/PD-L1 interaction and also MHC proteins that present antigens. HDAC inhibitors may upregulate MHC proteins, which is positive, but the current study shows that HDAC inhibitors may also upregulate PD-L1, helping cancer cells to pepper themselves with these white flags that deactivate the immune system.

Now imagine this solution: An HDAC inhibitor upregulates MHC and as an unfortunate byproduct upregulates PD-L1. But an anti-PD1 checkpoint inhibitor nixes the immune system’s ability to recognize all this extra PD-L1. The HDAC inhibitor restores MHC, serving more antigens to T cells, making the anti-PD1 therapy work better; and the anti-PD1 therapy keeps our T cells from recognizing any extra PD-L1 on cancer cells, making the HDAC inhibitor work better. In this scenario, the combination of HDAC inhibitor with anti-PD1 is greater than the sum of each drug used alone.

“We think this immunologic effect is very important. This paper emphasizes the immunologic action of HDAC. If your HDAC inhibitor is upregulating PD-L1, you’re not going to make it work alone. But if you also block PD1, HDAC inhibition looks much more successful,” Wang said.

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