Arming Tumor-Associated Macrophages to Reverse Epithelial Cancer Progression

Abstract

Tumor-associated macrophages (TAM) are highly expressed within the tumor microenvironment of a wide range of cancers, where they exert a protumor phenotype by promoting tumor cell growth and suppressing antitumor immune function.Here, we show that TAM accumulation in human and mouse tumors correlates with tumor cell expression of integrin avb3, a known driver of epithelial cancer progression and drug resistance. A monoclonal antibody targeting avb3 (LM609) exploited the coenrichment of avb3 and TAMs to not only eradicate highly aggressive drug-resistant human lung and pancreas cancers in mice, but also to prevent the emergence of circulating tumor cells. Importantly, this antitumor activity in mice was eliminated following macrophage depletion. Although LM609 had no direct effect on tumor cell viability, it engaged macrophages but not natural killer (NK) cells to induce antibody-dependent cellular cytotoxicity (ADCC) of avb3-expressing tumor cells despite their expression of the CD47 "don't eat me" signal. In contrast to strategies designed to eliminate TAMs, these findings suggest that anti-avb3 represents a promising immunotherapeutic approach to redirect TAMs to serve as tumor killers for late-stage or drugresistant cancers.Significance: Therapeutic antibodies are commonly engineered to optimize engagement of NK cells as effectors. In contrast, LM609 targets avb3 to suppress tumor progression and enhance drug sensitivity by exploiting TAMs to trigger ADCC.

Tumor-Associated Macrophages in Human Breast, Colorectal, Lung, Ovarian and Prostate Cancers

“…Clinically, high expression of CRYAB on tumor cells was associated with lymph node metastasis and tumor stage (III-IV) (156). In human and mouse tumors TAM accumulation correlated with the expression of integrin avb3 on cancer cells, a known driver of epithelial cancer progression and drug resistance (164). In mouse model of Lewis lung carcinoma (LLC), macrophage depletion with clodronate in combination with genetic ablation of CCR2 and CX3CR1 (receptors responsible for monocyte recruitment) inhibited cancer cell growth and metastasis enhancing survival in mouse (160).…”

Integrin α3β1 on Tumor Keratinocytes Is Essential to Maintain Tumor Growth and Promotes a Tumor-Supportive Keratinocyte Secretome

“…Macrophages are reduced during regression of a3b1deficient tumors Several a3b1-dependent proteins in the MK secretome have known roles in cross-talk to inflammatory cells, such as tumor-associated macrophages (e.g., CSF1, CSF2, CSF3, CXCL5, and IL-1a). A recent study linked avb3 integrin expression on tumor cells with accumulation of tumorassociated macrophages in human and mouse tumors(Wettersten et al, 2019). We detected a significant decrease in CD11b-positive leukocytes in a3b1-deficient…”

Biology and therapeutic targeting of tumour‐associated macrophages

“…For example, blocking the CXCL2 receptor CXCR2, which is not required for macrophage differentiation, reprogrammed TAMs from a tumour-promoting phenotype to one that enforced TNF-dependent cancer cell senescence in a Pten −/− Trp53 −/− model of prostate cancer [277]. Likewise, the antagonistic or agonistic targeting of surface molecules expressed on TAMs-such as CD163, MRC1/CD206, MARCO and STAB1 (all scavenger receptors), CD40 (a co-stimulatory molecule), CD47 (a phagocytosis inhibitory receptor), CD11b and various integrins (leukocyte adhesion molecules), TIE2 (angiopoietin receptor), and TLRs-could reprogram TAMs into immunostimulatory, 'super-phagocytic', or tumouricidal cells [229,250,276,[278][279][280][281][282][283][284][285][286][287][288][289][290].…”