TGF confers resistance to radiotherapy in non-small cell lung cancer

Radiotherapy is standard of care for inoperable non-small cell lung cancers (NSCLC) but adenocarcinoma NSCLC respond more poorly than squamous cell NSCLC. Transforming growth factor (TGF) activity is induced by radiation and plays a recently recognized role in the DNA damage response. Here we show in murine lung tumor model that radiation activates TGF acutely and persistently and that TGF neutralizing antibody, 1D11, systemic treatment increased tumor control following either fractionated or single high dose radiation regimes. TGF dependent genes in the irradiated tumor indicated crosstalk between innate and adaptive immunity but therapeutic benefit of 1D11 in irradiated tumors in immunocompromised mice suggested that innate immune cells are more influential than the adaptive immune response. Irradiated tumors in which TGF was blocked were highly hypoxic, exhibit pronounced microvascular damage and promoted neither cancer-associated fibroblasts nor recruit bone marrow derived cells (BMDC). Tumor educated immature BMDC were significant sources of TGF and inhibiting BMDC recruitment achieved tumor growth control in response to RT comparable to TGF inhibition. Thus, radiation-induced TGF both compromises tumor control by RT and promotes reestablishment of the tumor microenvironment. Concordant with the critical role of TGF activity in RT, radiation resistant NSCLC adenocarcinomas exhibit higher TGF activity compared to squamous cell NSCLC, which suggests a rationale for using TGF inhibition to augment radiotherapy.

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