Immune checkpoint inhibition (ICI) has transformed the treatment of patients with advanced or metastatic mismatch repair deficient (dMMR) or microsatellite instability high (MSI-H) colorectal cancer (CRC), leading to significant improvements in progression-free survival (PFS). The high tumor mutational burden (TMB) seen in dMMR CRCs is believed to enhance ICI response, as the abundance of neoantigens promotes greater immune cell infiltration into the tumor.

Regardless of its specific function, CD74 quantification could serve as a marker to identify CRC patients who may benefit from immune checkpoint inhibition (ICI). In support of this, a recent analysis of 21 pan-cancer samples—featuring only one dMMR CRC—suggested that CD74 protein expression could predict response to the dual PD-1/CTLA-4 inhibitor cadonilimab.

In current clinical practice, single protein biomarkers like PD-L1 are successfully used to predict prognosis and treatment response in various cancer types. However, this approach has not been as effective in colorectal cancer (CRC).

Fewer than 50% of metastatic deficient mismatch repair (dMMR) colorectal cancer (CRC) patients respond to immune checkpoint inhibition (ICI), highlighting the need to identify and expand this patient population. Recently, Amelia Acha-Sagredo et al demonstrate that a specific interferon-high immunophenotype—characterized by an enrichment of cytotoxic lymphocytes and antigen-presenting macrophages—underpins the response to ICI. Interestingly, this immunophenotype is not exclusive to dMMR CRCs but also occurs in a subset of MMR proficient (pMMR) CRCs. Using single-cell spatial analysis and in vitro co-culture models, they show that interferon-producing cytotoxic T cells stimulate the upregulation of antigen presentation in neighboring macrophages and tumor cells, including the MHC class II invariant chain CD74. High CD74 expression in dMMR CRCs correlates with better ICI response, and a subset of CD74-high pMMR CRC patients demonstrate improved progression-free survival with ICI treatment. Thus, CD74 abundance serves as a biomarker for identifying the interferon-high immunophenotype that predicts clinical benefit in CRC, irrespective of tumor mutational burden or MMR status.