Bone morphogenetic protein 7 promotes resistance to immunotherapy.

Immunotherapies revolutionized cancer treatment by harnessing the immune system to target cancer cells. However, most patients are resistant to immunotherapies and the mechanisms underlying this resistant is still poorly understood. Here, we report that overexpression of BMP7, a member of the TGFB superfamily, represents a mechanism for resistance to anti-PD1 therapy in preclinical models and in patients with disease progression while on immunotherapies. BMP7 secreted by tumor cells acts on macrophages and CD4+ T cells in the tumor microenvironment, inhibiting MAPK14 expression and impairing pro-inflammatory responses. Knockdown of BMP7 or its neutralization via follistatin in combination with anti-PD1 re-sensitizes resistant tumors to immunotherapies. Thus, we identify the BMP7 signaling pathway as a potential immunotherapeutic target in cancer.

Anti-glucocorticoid-induced Tumor Necrosis Factor-Related Protein (GITR) Therapy Overcomes Radiation-Induced Treg Immunosuppression and Drives Abscopal Effects.

Despite the potential to cure metastatic disease, immunotherapy on its own often fails outright or early on due to tumor immune evasion. To address this obstacle, we investigated combinations of anti-GITR, anti-PD1 and radiation therapy (XRT) in our previously developed anti-PD1 resistant 344SQ non-small cell lung adenocarcinoma preclinical tumor model. We hypothesized that targeting multiple mechanisms of immune evasion with this triple therapy would lead to an enhanced tumor-specific immune response and improve survival more so than any mono- or dual therapy. In a two tumor 344SQR murine model, treatment with anti-GITR, anti-PD1, and XRT led to significantly improved survival and an abscopal response, with half of the mice becoming tumor free. These mice showed durable response and increased CD4+ and CD8+ effector memory on tumor rechallenge. Regulatory T cells (Tregs) expressed the highest level of GITR at the tumor site and anti-GITR therapy drastically diminished Tregs at the tumor site. Anti-tumor effects were largely dependent on CD4+ T cells and partially dependent on CD8+ T cells. Anti-GITR IgG2a demonstrated superior efficacy to anti-GITR IgG1 in driving antitumor effects. Collectively, these results suggest that combinatorial strategies targeting multiple points of tumor immune evasion may lead to a robust and lasting antitumor response.

O papel das citocinas inflamatórias na tumorigênese e resistência a drogas no câncer de pulmão de não-pequenas células / [The role of inflammatory cytokines in tumorigenesis and drug resistance in non-small cell lung cancer]

O câncer de pulmão é a principal causador de mortes por câncer no mundo Mutações ativadoras de K-ras são uma das alterações mais comuns associadas ao câncer de pulmão e estão diretamante relacionadas com a exposição ao tabaco. Terapias baseadas em K-ras, têm sido desenvolvidas e até o momento todas falharam na prática clínica, indicando claramente a necessidade de novas estratégias terapêuticas que tragam benefícios clínicos para pacientes com este perfil mutacional. Aqui analisamos um painel representativo de linhagens de CPNPC, a fim de testar uma estratégia terapêutica baseada no Ligante Indutor de apoptose relacionado ao TNF(TRAIL) e nos receptores de morte celular DR4 e DR5. As diferentes linhagens de CPNPC foram tratadas com concentrações sub ótimas de cisplatina (IC30) e ensaios de expressão de gênica (qPCR) mostraram que tal regime induz um aumento na expressão de DR4 e DR5. LBY135 (Novartis) é um anticorpo monoclonal agonista de DR5 que mimetiza TRAIL na indução de morte celular em células que expressam DR5. Testamos a combinaçao CDDP(IC30) com LBY135 como uma estratégia capaz de induzir morte celular em linhagens de CPNPC. LBY135 como monoterapia mostrou um efeito bastante modesto, no entanto, quando CDDP (IC30) e LBY135 foram combinados, observou-se redução significativa na atividade metabólica em ensaios de MTT e aumento na morte de celular, sugerindo um efeito sinérgico dessas drogas. Tal efeito pró-apoptótico foi bloqueado por zVAD-fmk, um inibidor de caspases em geral. O efeito sinérgico observado foi mais pronunciado nas linhagens que apresentam a clássica mutação G12D em K-ras, sugerindo uma forma alternativa de subverter a quimio- resistência em linhagens de CPNPC com esse perfil mutacional. Os mecanismos envolvidos na iniciação da carcinogênese pulmonar ainda não são bem conhecidos. Nós investigamos o papel do desequilíbrio redox induzido pela exposição a Uretano, um conhecido indutor de adenocarcinoma pulmonar. Os nossos resultados sugerem que as diferenças nas respostas iniciais de estresse oxidativo, colaboram para a formação de um microambiente pulmonar supressor. Sugerimos que a capacidade de camundongos resistentes em disparar uma resposta adequada ao estresse na fase inicial constitui um mecanismo de proteção contra a carcinogênese. Vários estudos têm demonstrado que os pacientes com doença pulmonar obstrutiva crônica (DPOC), têm um risco aumentado de desenvolvimento de câncer de pulmão. Este fato sugere uma forte ligação entre microambiente pulmonar inflamatório e desenvolvimento de câncer de pulmão. Sabe-se que o estado DPOC-like tem efeito promotor no câncer de pulmão em um modelo murino mutante de k-ras. Esse foi associado com altos níveis de interleucina 6 (IL-6) e de seu efetor STAT3. Já foi observado que pacientes com câncer de pulmão apresentam expressão elevada de IL-6 e de seu receptor. Sugerindo uma possibilidade de intervenção terapêutica, com base nesse racional, bloqueamos a sinalização via IL6 utilizando um anticorpo monoclonal no modelo murino de K-ras mutado. O bloqueio da IL6, alterou, a quantidade do infiltrado celular inflamatório e a qualidade do microambiente pulmonar de pró-tumoral para um tipo anti-tumoral. Concluímos que a IL6 apresenta papel essencial para o desenvolvimento e promoção do cancer de pulmão através da indução de um microambiente pulmonar pró-tumoral. Assim, propomos o bloqueio farmacológico da IL-6 através do uso de anticorpos monoclonais como uma nova estratégia terapêutica para o tratamento de câncer de pulmão em pacientes que apresentam mutação em K-ras e possível estratégia preventiva para pacientes com DPOC.

Lung cancer is the leading cause of cancer death worldwide and cigarette smoking is its main cause. Activating mutations of K-ras are one of the most common alterations associated with tobacco exposure-related lung cancer. Several attempts to develop therapies based on K-ras, have been developed and thus far failed, clearly stating the need for new therapeutic strategies to bring clinical benefits to patients displaying such molecular profile. Here we have analyzed a representative panel of NSCLC cell lines, to test a pre-clinical therapeutic strategy engaging the TNF-related apoptosis-inducing ligand (TRAIL) receptor (Death receptor 4 and 5). NSCLC cell lines treated with suboptimal concentrations of cisplatin (IC30) gene expression analysis by qPCR showed an increased expression of DR4 and DR5 in these cells. LBY135 (Novartis) is a DR5 agonist monoclonal antibody that mimics TRAIL and induces cell death in DR5 expressing cells. LBY135 monotherapy did show some effects, however, when cisplatin IC30 and LBY135 were combined, we observed a significant decrease in MTT measurements and increased cell death incidence, suggesting a synergistic effect of these drugs. Such pro-apoptotic effect was blocked by zVAD-fmk, a pan-caspase inhibitor. The synergistic effect observed was more pronounced in cell lines bearing the classical G12D K-ras mutation, suggesting an alternative way to subvert chemo-resistance of K-ras mutated NSCLC. On the other hand, the mechanisms involved in in the initiation of lung carcinogenesis are not yet well understood and the literature suggests that the initial events related with inflammation could drive an oxidative-prone microenvironment formation and determine the final fate of the organ. We investigated the role of redox imbalance induced by urethane exposure, a known lung adenocarcinoma inducer. Our results suggest that the differences in the initial oxidative stress responses observed in two mice strains collaborate to the formation of a suppressive lung microenvironment. Therefore, we put forward the idea that the ability of resistant mice to up regulate a proper stress response at the initial stage constitutes a protective mechanism against carcinogenesis. Several studies have shown that patients with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, have a higher risk of developing lung cancer. This fact suggests a strong link between COPD-type inflammatory lung microenvironment and lung cancer development. It is known that a bacterial lysate-induced COPD-like airway inflammation promotes lung cancer in a K-ras mutant mouse model (CC-LR), which was associated with high levels of interleukin 6 (IL-6) and its downstream effector, STAT3. It has been shown that human lung cancer specimens have high tumor expression of IL-6 and IL-6 receptor. This prompted us to block IL-6 pathway using a monoclonal anti-IL-6 immunotherapy in a K-ras mutant model. Treatment with anti-IL-6 antibody not only inhibited intrinsic lung cancer development, but also inhibited the tumor promoting effect of COPD-like airway inflammation. Anti-IL-6 therapy changed the quantity of lung infiltrating inflammatory cells as well as the quality of lung microenvironment from a pro-tumor type to an anti-tumor type. We conclude that there is an essential role for IL-6 in development and promotion of lung cancer through inducing a pro-tumor lung microenvironment. Therefore, we propose pharmacologic targeting of IL-6 as a new therapeutic strategy for treatment of lung cancer in patients with K-ras mutation, and possible preventive strategy in patients with COPD.