Reprogramming the microenvironment with tumor-selective angiotensin blockers enhances cancer immunotherapy
Menée à l'aide de modèles murins de cancer du sein métastatique et de cancer du pancréas, cette étude met en évidence l'intérêt d'un antagoniste des récepteurs aux angiotensines pour modifier l'état des myofibroblastes CAFs et améliorer l'efficacité des immunothérapies
Cancer-associated fibroblasts (CAFs) can either inhibit or enable antitumor immunity, suggesting that they may be reprogrammed between these states. Angiotensin receptor blocker (ARB) drugs can reprogram CAFs to a quiescent state, but it is not known whether ARBs can enhance immune responses to cancer. Moreover, angiotensin signaling drives other important physiological processes and ARBs cause systemic adverse effects that limit their use in cancer. Here we created safer ARBs by chemically linking them to a polymer that degrades selectively in the slightly acidic microenvironment of solid tumors but not in the neutral environment outside of tumors. This tumor selectivity makes ARBs more effective at reprogramming CAFs while eliminating their side effects. These enhanced ARBs reduce immunosuppression and improve cancer immunotherapy efficacy.Cancer-associated fibroblasts (CAFs) can either suppress or support T lymphocyte activity, suggesting that CAFs may be reprogrammable to an immunosupportive state. Angiotensin receptor blockers (ARBs) convert myofibroblast CAFs to a quiescent state, but whether ARBs can reprogram CAFs to promote T lymphocyte activity and enhance immunotherapy is unknown. Moreover, ARB doses are limited by systemic adverse effects such as hypotension due to the importance of angiotensin signaling outside tumors. To enhance the efficacy and specificity of ARBs in cancer with the goal of revealing their effects on antitumor immunity, we developed ARB nanoconjugates that preferentially accumulate and act in tumors. We created a diverse library of hundreds of acid-degradable polymers and chemically linked ARBs to the polymer most sensitive to tumor pH. These tumor microenvironment-activated ARBs (TMA-ARBs) remain intact and inactive in circulation while achieving high concentrations in tumors, wherein they break down to active ARBs. This tumor-preferential activity enhances the CAF-reprogramming effects of ARBs while eliminating blood pressure-lowering effects. Notably, TMA-ARBs alleviate immunosuppression and improve T lymphocyte activity, enabling dramatically improved responses to immune-checkpoint blockers in mice with primary as well as metastatic breast cancer.