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Cancer-Fighting T Cells Tuned To Viral Particles May Target Tumor Neoantigens

NEW YORK (GenomeWeb) – New research suggests cancer-fighting T-cells in the immune system may react more robustly to neoantigens formed from somatic or germline mutations in the tumors themselves than to antigens associated with particles from viruses such as human papillomavirus (HPV).

A National Cancer Institute-led research team used a combination of tandem minigene-borne antigens, assays, and T-cell receptor sequencing to profile overall T-cell responses in two individuals with HPV-positive, metastatic cervical cancer who had achieved lasting cancer regression after treatment with adoptive tumor-infiltrating lymphocyte transfer therapy.

"Our findings reveal a previously unrecognized participation of T-cells targeting non-viral tumor antigens in the immunotherapy of [HPV-positive] cervical cancer," senior author Christian Hinrichs, an NCI experimental transplantation and immunology branch researcher, and his co-authors wrote.

Because T-cells that expressed the programmed death 1 (PD-1) protein were also those showing the most pronounced responses to the tumor and viral antigens after the adoptive cell therapy, they reasoned that adding in immunotherapy approaches that block the PD-1-based immune checkpoint may also "unleash diverse anti-tumor T-cell reactivities."

For their analysis, reported today in Science, the researchers focused on two adoptive T-cell therapy-treated women with metastatic cervical cancer. The first patient had a form of HPV16+ squamous cell carcinoma with post-treatment cancer regression that had already continued for more than four-and-a-half years, while the other patient had an HPV18+ adenocarcinoma that was in ongoing regression nearing four years after this type of immunotherapy.

The adoptive T-cell therapies used in these patients were designed to expand tumor-infiltrating lymphocyte populations targeting oncogenic HPV proteins, the team noted, though the actual antigens being targeted in the treatment-responsive patients was unclear.

In an effort to get a better sense of the T-cell activity and targeted antigens in these individuals, the researchers began by gauging infused tumor-infiltrating lymphocyte responses to HPV oncoproteins and to tandem minigenes coding for potential neoantigens produced from somatic and germline mutations in the individuals' tumors.

The expanded tumor-infiltrating lymphocytes from one of the patients reacted to neoantigens associated with somatic mutations in genes such as SETDB1, METTL17, and ALDH1A1, for example. In the other patient, responses were most pronounced in the presence of antigens linked to a germline mutation.

Such findings hinted that tumor mutations may encode key neoantigens that fall in T-cells' crosshairs after adoptive cell therapy. The team's subsequent T-cell receptor profiling experiments — done using single-cell reverse transcription PCR, Adaptive Biotechnologies' pairSEQ assays, and/or T-cell receptor beta-chain sequencing — picked up some receptors responding to these mutations and others linked to the original HPV oncoprotein targets.

From these and other results, the researchers estimated that roughly 14 percent of the expanded tumor-infiltrating lymphocyte T-cell receptor clonotypes responded to HPV protein targets in each of the patients.

In contrast, more than one-third of the T-cell receptor types corresponded to somatic mutation-based neoantigens in the patient with SETDB1 and other somatic mutations. In the individual with T-cell targeted germline mutations, meanwhile, these mutations appeared to be targeted by more than two-third of the T-cell receptors.

The team noted that it may be able to tease out even more information on tumor antigen targeting by the immune system by tracking T-cell response not only in responders, but also in individuals who have not fared as well with adoptive T-cell therapy.

"Analysis of patients who have not response to immunotherapy may provide additional insight into the importance of T-cells targeting this class of tumor antigens," the authors concluded. "Our study provides the impetus for research into the contribution of both viral and non-viral tumor antigen reactivities to the anti-tumor activity of adoptive T-cell therapies and immune checkpoint inhibitors for virally-associated malignancies."