Artikkeliväitöskirja (G5)

Re-educating macrophages to activate antitumor immunity: One Clever Immunotherapy

Julkaisun tekijätViitala Miro

KustantajaUniversity of Turku







The immune system is our constant protector against external foes but also against our own incipient malignant cells. Unfortunately, developing cancers often learn to shut down the antitumor immune response or even to manipulate the immune system to support their own growth and progression instead. Checkpoint blockers that reactivate adaptive antitumor immunity have revolutionized cancer treatment—however, benefiters are in the minority. Therefore, novel treatment options are required for patients whose cancers are refractory. Tumor-associated macrophages of the innate immune system—educated in the tumor micro-environment—have emerged as prominent supporters of cancer progression that promote nine out of ten hallmarks of cancer. However, thanks to their remarkable intrinsic plasticity, macrophages retain the capability to promote the antitumor immune response even in thrall of cancer. Consequently, significant interest has been directed to the possibility of targeting tumor-associated macrophages to promote antitumor immunity as cancer immunotherapy.

In this PhD thesis, I present the preclinical proof-of-concept, putative mechanism-of-action and results from early clinical trials of one such experimental immunotherapy: antibody blockade of the scavenger receptor Clever 1, expressed on a subset of tumor-associated macrophages. The results herein establish macro¬phage Clever 1 as an endogenous immune suppressor that restrains both macro¬phage overactivation and adaptive immunity. We show that Clever-1 blockade “re-edu¬cates” macrophages to promote antitumor immunity by activating cytotoxic T cells in preclinical tumor models. We propose this is mechanistically linked to Clever 1’s association with the vacuolar ATPase, the disruption of which antagonizes antigen degradation in phagolysosomes and saves them for cross-presenta¬tion. Lastly, I present results from early clinical trials, which indicate that Clever-1 blockade may boost antitumor immunity specifically in a subset of patients with noninflamed tumors for whom checkpoint blockade is rarely efficacious.

Last updated on 2023-24-03 at 14:54