Tumor-associated fibrosis impairs immune surveillance and response to immune checkpoint blockade in non–small cell lung cancer

Abstract

Non–small cell lung cancer (NSCLC) is a leading cause of cancer-related deaths. Immune checkpoint blockade has improved survival for many patients with NSCLC, but most fail to obtain long-term benefit. Understanding the factors leading to reduced immune surveillance in NSCLC is critical in improving patient outcomes. Here, we show that human NSCLC harbors large amounts of fibrosis that correlates with reduced T cell infiltration. In murine NSCLC models, the induction of fibrosis led to increased lung cancer progression, impaired T cell immune surveillance, and failure of immune checkpoint blockade efficacy. Associated with these changes, we observed that fibrosis leads to numerically and functionally impaired dendritic cells and altered macrophage phenotypes that likely contribute to immunosuppression. Within cancer-associated fibroblasts, distinct changes within the Col13a1 -expressing population suggest that these cells produce chemokines to recruit macrophages and regulatory T cells while limiting recruitment of dendritic cells and T cells. Targeting fibrosis through transforming growth factor–β receptor signaling overcame the effects of fibrosis to enhance T cell responses and improved the efficacy of immune checkpoint blockade but only in the context of chemotherapy. Together, these data suggest that fibrosis in NSCLC leads to reduced immune surveillance and poor responsiveness to checkpoint blockade and highlight antifibrotic therapies as a candidate strategy to overcome immunotherapeutic resistance.

The phosphatidylserine targeting antibody bavituximab plus pembrolizumab in unresectable hepatocellular carcinoma: a phase 2 trial

“…Notably, our analysis also indicates that increased SMA expression, reflecting intratumoral fibrosis and cancer-associated fibroblasts, may be associated with worse response to bavituximab plus pembrolizumab 38 – 40 . This finding is consistent with recent evidence that tumor-associated fibrosis in the lungs impairs immune surveillance and poor responsiveness to checkpoint blockade 41 . These findings may support the potential utility of combining anti-fibrotic therapies with ICIs in fibrotic HCC in future studies.…”

ALCAM-mediated cDC1 CD8 T cells interactions are suppressed in advanced lung tumors

“…To facilitate the recovery of sufficient numbers of primary cells from tissues and to precisely control the tumor stage, we moved to a transplantable KP line, previously shown to recapitulate most features of autochthonous tumors. 25 , 26 Tissues were harvested after 8 or 28 days, corresponding to early dysplasia, or established adenocarcinoma. Cell-sorted cDC1 were pre-pulsed with an OVA class-I peptide (SIINFEKL) to bypass defective antigen uptake and processing and mixed with functional, OVA-specific CD8 T cells (OT-I) ( Figure 2a ).…”

Potential Association Between COVID-19 Infections and the Declining Incidence of Lung Cancers

“…Studies have suggested that COVID-19 elicits a robust immune response involving both innate and adaptive immunity [11,12]. This heightened immune surveillance might inadvertently target and eliminate precancerous or early-stage lung cancer cells, leading to a reduction in cancer development and progression [13]. However, further studies are required to further clarify these immunological mechanisms involved and their impact on lung cancer biology.…”