Sustained compensatory p38 MAPK signaling following treatment with MAPK inhibitors induces the immunosuppressive protein CD73 in cancer: combined targeting could improve outcomes

Abstract

RAS-MAPK signaling promotes immune evasion and cancer cell survival, and MAPK inhibitors (MAPKi) are frequently used as cancer therapies. Despite progress elucidating the direct effects of MAPKi on immune cells, their indirect effect on the tumor microenvironment (TME) through changes in tumor cells remains incompletely understood. Here, we present evidence of a rapid compensatory response to MAPKi that is driven by sustained p38-MAPK signaling and by which cancer cells can upregulate the immunosuppressive protein CD73 to reduce the anti-tumor immune response. This compensatory response also results in decreased sensitivity towards MAPKi and, accordingly, combining anti-CD73 antibodies and MAPKi significantly enhances the anti-tumor effect compared to single-agent treatment in vivo. Combining MAPKi and anti-CD73 was accompanied by significant alterations in intratumor immune-cell composition, supporting the effect of MAPKi-induced CD73 expression on the TME. We show that high CD73 expression significantly correlates with worse outcome in MAPKi-treated colorectal cancer patients, highlighting the potential clinical importance of increased CD73 expression following MAPKi treatment. Our findings may explain the diminished effect of MAPKi in cancer patients and provides further rationale for combined anti-CD73 and MAPKi treatment.

Genetic dysregulation of immunologic and oncogenic signaling pathways associated with tumor-intrinsic immune resistance: a molecular basis for combination targeted therapy-immunotherapy for cancer

“…An alternate mechanism for targeted therapy-induced crossresistance to immunotherapy has also recently been reported by Terp et al, who found that sustained activation of p38 MAPK signaling compensated for MEK inhibition, leading to upregulation of CD73 in several murine tumor models. Targeting CD73 in conjunction with MEK also improved tumor control in this setting [135]. These ndings likely explain the synergistic anti-tumor effects that have previously been observed when BRAF/MEK inhibition is combined with targeted inhibition of the A2A adenosine receptor in a murine melanoma model [136].…”

Investigating the effects and mechanisms of Erchen Decoction in the treatment of colorectal cancer by network pharmacology and experimental validation

“…And MAPK signaling pathway has also been reported to play a significant role in promoting the development and progression of CRC by affecting cell proliferation and differentiation, blocking the cell cycle, and inhibiting cell apoptosis ( Sun et al, 2015 ). Recently, MAPK inhibitors have been frequently used as cancer therapies, including the direct and indirect effects on TME ( Terp et al, 2021 ). Therefore, combining our results with previous studies, we speculated that ECD might exert its therapeutic effect through the MAPK signaling pathway.…”

PDX Models: A Versatile Tool for Studying the Role of Myeloid-Derived Suppressor Cells in Breast Cancer

“…Tumors were harvested for dissociation into single-cell suspensions, as previously described [ 22 ]. In brief, minced tumors were incubated for 45 min in dissociation buffer [2 mg/mL collagenase IV (Merck Life Science, Søborg, Denmark, #C5138)] supplemented with 4 U/mL DNAse I (Thermo Scientific, #EN0521) with constant low agitation at 37 °C and subsequently pipetted up and down for 2 min using a 5 mL pipette.…”