Uncovering an enemy of lung cancer immunotherapy

MD Anderson researchers have uncovered a genetic condition that thwarts the most common immunotherapy used against lung cancer, opening new avenues for improved targeting of immune checkpoint blockade drugs and extending their use to more patients with new combinations.

Anti-PD1 or PD-L1 drugs that block an off-switch on immune system T cells, facilitating their attack on tumors, provide durable responses in about 20 percent of non-small cell lung cancer patients. 

“These findings are a major step on the path to more personalized immunotherapy, where we identify targets for specific groups of patients, and tailor treatment strategies for them, just as we did with molecular targeted therapy,” says John Heymach, M.D., Ph.D., professor and chair of Thoracic/Head and Neck Medical Oncology.

Published in Cancer Discovery, the research paper shows that a gene called STK11 mutated or deleted in a third of non-small cell lung cancer patients, fosters an immunologically "cold” tumor microenvironment, with minimal penetration of tumors by T cells, rendering anti-PD1/PDL1 drugs ineffective.

The paper describes how adding specific types of drugs to anti-PD1 therapy might overcome resistance in these cases. The project received vital early funding from MD Anderson’s Moon Shots Program™ through the Lung Cancer Moon Shot™.

STK11/LKB1 prime genomic driver of resistance

“We’ve identified what we think is the most prevalent genomic driver of a cold tumor microenvironment and primary resistance to anti-PD1 immunotherapy in non-small cell lung cancer,” says Ferdinandos Skoulidis, M.D., Ph.D., assistant professor of Thoracic/Head and Neck Medical Oncology and lead author of the paper.

“Our results suggest that a single molecular mechanism downstream from STK11/LKB1 mutations accounts for a very large percentage of patients whose tumors resist immunotherapy,” Skoulidis says, “instead of multiple mechanisms each accounting for a small fraction of patients.”

Researchers had previously identified patients who have mutations in both the tumor-suppressing STK11/LKB1 and the cancer-promoting KRAS genes as a distinct group. Working with colleagues at other cancer centers through a Stand Up to Cancer dream team grant, they tracked down the specific impact of the mutations.

Analysis of 174 patients treated at MD Anderson, Memorial Sloan-Kettering Cancer Center and Dana-Farber Cancer Center showed that only 7.4 percent of those with both STK11/LKB1 and KRAS mutations responded to anti-PD1 therapy. Response rates in other groups ranged from 28.6 percent (KRAS-only tumors) to 35.7 percent (KRAS plus TP53 mutant tumors).

Median overall survival for the STK11/LKB1 and KRAS group was only 6.4 months, compared to 16 months each for the other two groups.

The team conducted an unbiased genomic analysis of 924 tumors from Foundation Medicine to identify genes that drive the absence of PD-L1 expression in tumors. PD-L1 is the ligand that activates PD-1 on T cells to shut down immune response. The absence of PD-L1 is an indicator of a “cold tumor.”

They found STK11/LKB1 to be the only significantly enriched gene in tumors that both lacked PD-L1 and also had a high burden of mutated genes – usually a sign of vulnerability to immunotherapy because abundant mutations provide multiple targets for T cells.

A follow-up analysis of 66 patients treated with PD-1/PD-L1 inhibitors at MD Anderson showed that STK11/LKB1 mutated tumors had poor response (zero responders) to treatment, even when they also had PD-L1 expression compared to those with intact STK11/LKB1 (34.5 percent). This effect was also independent of KRAS mutation status.

The team is working to better understand how the STK11/LKB1 mutation specifically causes cold tumors and is exploring drug combinations to overcome resistance.

Skoulidis notes that STK11/LKB1 mutation status could become a biomarker for guiding treatment, used in combination with tumor mutational burden and PD-L1 status, both which suggest vulnerability to immunotherapy but are not conclusive indicators.