Dr. Fakih on Tumor Microenvironment Differences in MSS mCRC

Marwan G. Fakih, MD, Judy & Bernard Briskin distinguished director of Clinical Research, professor, Department of Medical Oncology and Therapeutics Research, associate director for Clinical Research, Comprehensive Cancer Center, co-director, Gastrointestinal Cancer Program, City of Hope, discusses a comparative analysis of the tumor microenvironment in primary tumors vs metastatic tissue in patients with microsatellite stable (MSS) metastatic colorectal cancer (mCRC).

In a retrospective analysis, investigators analyzed de-identified patients with MSS mCRC who underwent next-generation sequencing with Tempus xT. Investigators analyzed tissue that was sequenced from the primary tumor, as well as liver, lung, and peritoneal metastases, to examine genomic alterations, tumor mutational burden (TMB), PD-L1 expression, macrophages, and proportions of B, CD4+, CD8+, and natural killer (NK) cells.

Investigators have shown that there are considerable variations in the tumor microenvironment between the primary tumor in mCRC and metastases, Fakih says. For example, that the percentage of immune cells in lung metastases of patients with mCRC is much higher than it is in peritoneal metastases or liver metastases, and this percentage could even exceed the primary tumor. Additionally, CD8+ cell infiltration, which are important in generating an immune response, was higher in lung metastases vs liver metastases, Fakih notes.

Moreover, investigators saw substantial differences in the expression of macrophages in lung metastases vs liver and peritoneal metastases. In liver and peritoneal metastases, the expression of macrophages is more prevalent compared with primary tumors and lung metastases, Fakih continues. There are also some favorable differences for NK cells seen in the lung metastases vs other metastatic sites.

These characteristics of lung metastases may account for more favorable responses to checkpoint inhibitors. Previously, investigators looked at TMB, neoantigen tumor burden, and PD-L1 positivity in primary tumors, as well as lung, liver, and peritoneal metastases, and they did not note any substantial differences in these factors that would explain the variation in immune cell infiltration or responses to immunotherapy, Fakih explains.

This study showed that differences in responses to immunotherapy could stem from differences in tumor microenvironment characteristics in patients with mCRC, which are more favorable for lung metastases vs liver or peritoneal metastases, Fakih concludes.