Note: This article has been updated to clarify the nature of the tumor infiltrating lymphocytes elevated in the BRCA1/2-mutated ovarian tumors.
CHICAGO (GenomeWeb) – Researchers have started tracking immune responses to different genomically defined cancer subtypes in an attempt to find those most apt to respond to immunotherapy-based treatment approaches, attendees heard here this week at the American Society of Clinical Oncology annual meeting.
During a clinical science symposium on the intersection of the "mutanome" and the "immunome," members of two teams described attempts to decipher interactions between the immune system and tumors from endometrial or ovarian cancer subtypes known for particularly mutation-rich tumors.
For one of the studies, researchers from Brigham and Women's Hospital, Harvard Medical School, and the Dana-Farber Cancer Institute characterized tumor-infiltrating immune cell activity and immune checkpoint contributor expression in dozens of archival endometrial tumors samples from mutation-heavy polymerase epsilon (POLE) mutations and microsatellite instability subtypes, comparing them with patterns in more mutation-light microsatellite stable tumors.
The results suggest endometrial cancers from subtypes prone to more widespread mutation also trigger stronger immune responses that might be further enhanced by drugs that inhibit cancer cells' immune checkpoints, explained Brooke Howitt, a pathologist at the Brigham and Women's Hospital, who presented the research at ASCO.
Findings from hundreds of endometrial carcinomas profiled by the Cancer Genome Atlas led to the recognition that there are four molecularly distinct subtypes of endometrial cancer, Howitt explained.
Two of these subtypes — the POLE-hypermutated and microsatellite unstable endometrial cancers — caught the team's attention, since it's predicted that tumors containing rampant mutations might draw more immune attention to themselves than those with lower frequency mutation patterns.
To explore this possibility, Howitt and her colleagues used immunohistochemistry to profile tumor infiltrating lymphocyte and expression of the immune checkpoint players PD-1 and PD-L1 in four POLE-mutated endometrial cancers, 28 endometrial cancers with microsatellite instability, and 32 microsatellite stable endometrial cancers.
Indeed, their results pointed to more pronounced tumor infiltration by CD3+ , CD4+, and CD8+ lymphocytes in the group of POLE-mutated and microsatellite unstable tumors than in the microsatellite stable subtype, consistent with T-cell activity against the mutation-rich tumors.
When they compared the more mutated endometrial cancer subtypes to the microsatellite stable group, the researchers saw signs of enhanced PD-L1 and PD-1 expression in both infiltrating lymphocytes and in the tumors themselves, hinting that the oft-mutated subtypes may respond to immune-targeting PD-1 inhibitor drugs.
In contrast, the group didn't see a difference in CD20+ tumor infiltrating lymphocytes, which represent B-cell activity against the disease.
In another presentation in the same session, meanwhile, Dana-Farber Cancer Institute researcher Kyle Strickland provided evidence for a similar pattern of bolstered immune activity against extensively mutated tumors.
For their part, though, Strickland and his team focused on BRCA1- and/or BRCA2-mutated, high-grade serous ovarian cancers, using immunohistochemistry to see if the high mutational load found in tumors with hampered BRCA-mediated DNA repair activity might also be a flag for the immune system.
There, researchers compared tumor infiltrating lymphocyte patterns in 37 BRCA1/2-mutated tumor samples and in samples from 16 tumors lacking germline or somatic mutations in BRCA1, BRCA2, or related mutations or expression changes — features verified by high-throughput sequencing.
Results from that comparison suggested that all of the ovarian cancers had comparable levels of certain tumor infiltrating lymphocytes, such as the CD4+ or CD20+ lymphocytes.
But compared with the "homologous recombination intact" tumors, the BRCA1/2-mutated ovarian cancers appeared to be marked by higher CD8+ and CD3+ tumor infiltrating lymphocytes, Strickland explained.
Moreover, the team saw an apparent jump in PD-1 representation in the lymphocytes that were infiltrating neighboring tumors in the BRCA1/2-mutated tumors relative to the other ovarian cancers, though staining for the immune checkpoint contributors within tumors themselves appeared similar regardless of the subtype considered.
Strickland and his colleagues reasoned that such a feature may partly explain the relatively high progression-free survival and overall survival rates reported in BRCA1/2-mutated ovarian cancers, though they are continuing to study the relationship between BRCA mutations and tumor features.
Memorial Sloan Kettering medical oncologist Alexandra Snyder Charen discussed potential implications of the endometrial and ovarian cancer studies, noting that distinct mutation signatures in different tumor types could also affect immune response.
While she expressed enthusiasm about potential treatment clues provided by more-or-less mutated endometrial and ovarian cancers, Snyder Charen noted that additional research is needed on additional forms of the disease, since the work described was done using primary tumors.