Cancer immunotherapies that go solo against cancer face an intimidating prospect: relatively few patients will respond. Also, predicting which patients will respond is difficult. Overcoming cancer, however, can be a group effort that draws on the unique capabilities of diverse players—killer T cells and helper T cells, for example. Although killer T cells have attracted more attention from researchers, helper T cells are entering the spotlight, too.

Helper T cells are involved in recognizing cancer as a threat and recruiting killer T cells to mount an attack. Also, helper T cells can ensure that the immune system fully responds to cancer. Moreover, according to a new study led by researchers at the University of Washington School of Medicine (UWSOM), helper T cells can boost the effectiveness of immune therapy.

“[Our] study reveals for the first time that helper T cells are essential in cancer immunotherapy,” said Robert D. Schreiber, PhD, a professor of microbiology and the Andrew M. and Jane M. Bursky distinguished professor of pathology and immunology at UWSOM. “Activating killer T cells alone is not enough. To work better for all patients, we think effective cancer vaccines and immunotherapy drugs must activate both the killer and helper T cells.”

Schreiber is the senior author of a paper (“MHC-II neoantigens shape tumor immunity and response to immunotherapy”) that appeared October 23 in Nature. This paper delves deep into a group of genes that activate the helper T cells, or CD4+ cells. These genes are called MHC class II genes, and they are distinct from the MHC class I genes that activate killer T cells, or CD8+ cells.

“Here we show that spontaneous and immunotherapy-induced antitumor responses require the activity of both tumor-antigen-specific CD8+ and CD4+ T cells, even in tumors that do not express major histocompatibility complex (MHC) class II molecules,” the article’s authors wrote. “In addition, the expression of MHC class II-restricted antigens by tumor cells is required at the site of successful rejection, indicating that activation of CD4+ T cells must also occur in the tumor microenvironment.”

Schreiber and colleagues developed a computer program that can predict which mutant proteins—or antigens—on a patient’s tumor will specifically activate helper T cells. This sort of predictive software is well-established for activating killer T cells. But until now, this was largely impossible for helper T cells.

“For killer T cells, we’re relatively good at looking at a patient’s tumor, seeing what mutations are present and figuring out which mutations are most likely to trigger killer T cells to respond,” said the Nature paper’s first author Elise Alspach, PhD, a postdoctoral research associate in Schreiber’s lab. “But the ability to do this for helper T cells has lagged far behind.”

Added Schreiber, “It’s a bit like finding a needle in a haystack. With all the proteins in tumor cells, how do you find the ones that serve as the best antigens to activate the immune system? We believe the technique that we’ve developed is an important step forward for harnessing helper T cells in cancer immunotherapy.”

Studying mice with models of human cancer, Schreiber and colleagues showed that immune checkpoint therapy is more effective when helper T cells are activated along with killer T cells. They further showed that vaccines also are more effective when targets activating both helper and killer T cells are present.

And finally, the most effective antitumor responses occurred when immune checkpoint therapy was combined with a vaccine that incorporates targets for helper and killer T cells that are specific to antigens in the patient’s tumor. In other words, an optimal antitumor response appears to require that tumor cells express both MHC-I and MHC-II neoantigens.

“This requirement,” the authors of the Nature article noted, “reflects the potential need for CD4+ T cell responses in the tumor microenvironment and, from previous work, appears to be at least partially due to production of interferon-γ by tumor-specific CD4+ T cells. We find it of particular interest that the generation of effective tumor immunity requires MHC-II neoantigens following either vaccination with tumor-specific neoantigen vaccines or immune checkpoint therapy.”

“Just because a killer T cell is present doesn’t mean it’s actively killing tumor cells,” Alspach pointed out. “We found that not only do you need helper T cells to recruit the killer T cells, the helper cells need to be there to coax the killer T cells to mature into an active state in which they are capable of killing cells.”

“The idea of giving checkpoint inhibitors along with a tumor-specific vaccine—especially a vaccine that activates both killer and helper T cells—is just beginning,” Schreiber declared. “But based on our study, the combination is likely to be more effective than any of the components alone. Today, when we treat a particular tumor type with checkpoint inhibitors, maybe 20% of the patients respond well. We’re hoping that with a vaccine plus checkpoint inhibitors, the number of patients who respond well will go up to 60 or 70%. We haven’t tried that yet in patients, but that’s the hope.”

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