Immune Checkpoint Combinations Show Promise in Endometrioid Disease

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Many endometrioid cancers express high RNA levels for multiple immune checkpoints, and this may allow physicians to treat these patients with combination immune therapies.

Many endometrioid cancers express high RNA levels for multiple immune checkpoints, and this may allow physicians to treat these patients with combination immune therapies, according to data presented at the SGO 2018 Annual Winter Meeting in Aspen, Colorado.

“The finding of elevated expression of multiple immune checkpoints in the endometrioid carcinomas suggests that simultaneous targeting with combined immune checkpoint inhibitor therapy may be considered in these patients and should be considered for exploration in future clinical trials,” said study author Amanda Ramos, MD, a first-year gynecologic oncology fellow at Massachusetts General Hospital of Boston.

Ramos and her colleagues evaluated relative RNA expression levels in various immune checkpoint genes for which there are pipeline agents that antagonize the expressed proteins. Investigators selected 60 patients diagnosed with 6 histologic subtypes of endometrial cancer: microsatellite instability (MSI)-high (n = 13), MSI-low (n = 11), carcinosarcoma (n = 11), uterine serous carcinoma (n = 11), microsatellite stable (MSS)-high (n = 3), and MSS-low (n = 11).

Median age at diagnosis was 66 and most patients (n = 32) had stage IA disease. Seven patients had recurrent disease, and median time to recurrence was 10 months. Fifty-four patients were alive at last follow-up.

Researchers amplified the expression of various genes of interest including those encoded in the PD-1, TIM-3, CTLA-4, and LAG-3 checkpoint proteins and those involved in cell migration and recognition. Relative levels of RNA expression were then quantified, and high and low levels of expression were confirmed with immunohistochemistry.

Researchers assessed CD8 RNA levels in the different histologies. CD8 cells direct the T-cells against tumors and harbor the PD-1 checkpoint.

“Endometrioid cancers have a higher relative expression of CD8 and, more specifically, microsatellite unstable, high-grade endometrioid cancers are seen to express higher levels of CD8 compared with low-grade endometrioid cancers that are microsatellite stable,” Ramos said.

She added that it is important to note the presence of immune checkpoint ligands, specifically PD-L1 and PD-L2. “Expression is preserved across the endometrioid histologies, and both ligands were found to have significantly higher levels of RNA expression in the endometrioid tumor tissues compared to carcinosarcoma,” she said.

Also, investigators found that endometrioid tumors expressed a significantly elevated level of PD-1 in patients with uterine serous carcinoma compared with carcinosarcoma.

When researchers analyzed the subtypes by grade and mismatched repair status, they spotted a trend toward increased PD-1 expression in MSI-high endometrioid tumors compared with the other subtypes, Ramos said.

Expression of TIM-3 was also elevated in the endometrioid histologies compared with the nonendometrioid subtypes. As with PD-1, TIM-3 expression was elevated in expression in MSI-high endometrioid tumors.

“Recent data has also shown that TIM-3 is upregulated in tumors that have undergone PD-1 blockade, suggesting a potential target for combined immunotherapies,” Ramos said.

Expression of LAG-3 was “ubiquitous” across the histologies, with significantly elevated expression in the expression in MSI-high endometrioid tumors compared with the MSI-low tumors.

Similarly, CTLA-4 expression was elevated in endometrioid tumors and significantly elevated in MSI-high tumors. When the various checkpoints were compared for relative RNA expression, the CTLA-4 checkpoint had a “markedly greater magnitude” of RNA expression, Ramos said.

“The results of this analysis reveal that endometrioid carcinomas and, specifically, the MSI-high grade endometrioid cancers have relatively elevated levels of RNA expression in multiple immune checkpoints,” Ramos said. “Overall, carcinomas and uterine serous carcinomas have an innate paucity of immune checkpoint expression and other immunogenic genes, suggesting that the immune cloaking may be an acquired mechanism further down the road as the tumor evolves.”

Ramos A. Checkpoint inhibitor signatures across endometrial carcinoma histologic subtypes. Presented at: the SGO 2018 Annual Winter Meeting; Feb. 8-10, 2018; Aspen, CO.