The EACR’s ‘Highlights in Cancer Research’ is a regular summary of the most interesting and impactful recent papers in cancer research, curated by the Board of the European Association for Cancer Research (EACR).
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Gong, Z., Li, Q. et al. Immunity. 55(8): 1483-1500. (2022).
doi: 10.1016/j.immuni.2022.07.001.
Summary of the findings
Metastatic disease remains the leading cause of cancer-related death, and the lung is one of the most common organs to which solid tumors metastasize. It has been widely acknowledged that the formation of an immunosuppressive lung microenvironment is critical for disseminated tumor cells (DTCs) from a primary tumor to develop successful metastatic lung colonization. However, little is known about how the local lung stroma contributes to the formation of such an immunosuppressive niche. In this work, a unqiue lung stromal regulatory program was identified to play a decisive role in establishing a robust immunosuppressive lung milieu. Different types of bone marrow-derived myeloid cells, when infiltrating the lung, were reprogrammed by lung-resident cyclooxygenase 2 (COX-2)-expressing adventitial fibroblasts (AdvF) to become immunosuppressive and/or dysfunctional. This lung stromal program exists at the steady state, and is reinforced by tumor-bearing conditions, especially tumor-associated inflammation. Through this driver role, lung fibroblasts elicit formation of a receptive niche that fosters DTC colonization via evasion of lung-resident anti-tumor immunity. Genetic ablation or pharmacological targeting of the lung fibroblast signaling molecules largely restored local anti-tumor immunity, mitigated lung metastasis, and improved the therapeutic efficacy of immunotherapeutics in treating lung metastasis.
Future impact
Understanding how metastatic tumor cells colonize distant organs by evasion of the local anti-tumor immunity is an essential step towards developing effective therapeutics to treat metastatic disease. This study deciphered a lung-intrinsic immunosuppressive program instigated by Ptgs2high tissue-resident fibroblasts, which is hijacked by breast tumor cells for their metastasis. As lung fibroblasts actively remodel the immune landscape in the lung, targeting fibroblast-associated signaling molecules would be a promising approach for lung metastasis treatments, particularly in combination with immunotherapeutics that are already in wide use. The findings also offer insights for studying stromal-immune cell interactions in other metastatic organs.
