Taube JM, Anders RA, Young GD, Xu H, Sharma R, McMiller TL, Chen S, Klein AP, Pardoll DM, Topalian SL, Chen LColocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med 4: 127ra37
Although many human cancers such as melanoma express tumor antigens recognized by T cells, host immune responses often fail to control tumor growth for as yet unexplained reasons. Here, we found a strong association between melanocyte expression of B7-H1 (PD-L1), an immune-inhibitory molecule, and the presence of tumor-infiltrating lymphocytes (TILs) in human melanocytic lesions: 98% of B7-H1(+) tumors were associated with TILs compared with only 28% of B7-H1(-) tumors. Indeed, B7-H1(+) melanocytes were almost always localized immediately adjacent to TILs. B7-H1/TIL colocalization was identified not only in melanomas but also in inflamed benign nevi, indicating that B7-H1 expression may represent a host response to tissue inflammation. Interferon-γ, a primary inducer of B7-H1 expression, was detected at the interface of B7-H1(+) tumors and TILs, whereas none was found in B7-H1(-) tumors. Therefore, TILs may actually trigger their own inhibition by secreting cytokines that drive tumor B7-H1 expression. Consistent with this hypothesis, overall survival of patients with B7-H1(+) metastatic melanoma was significantly prolonged compared with that of patients with B7-H1(-) metastatic melanoma. Therefore, induction of the B7-H1/PD-1 pathway may represent an adaptive immune resistance mechanism exerted by tumor cells in response to endogenous antitumor activity and may explain how melanomas escape immune destruction despite endogenous antitumor immune responses. These observations suggest that therapies that block this pathway may benefit patients with B7-H1(+) tumors.
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"Expression of PD-L1 has been correlated with poor clinical outcomes in a number of human cancers, including melanoma, lung, breast, bladder, ovarian, pancreatic cancers, oesophagus adenocarcinoma, kidney tumours as well as in hematopoietic malignancies (Zou and Chen, 2008). However, other reports indicated a lack of association between PD-L1 expression and outcome (Konishi et al, 2004; Mischinger et al, 2010) or that PD-L1 expression was associated with an improved survival and increased TILs (Taube et al, 2012). "
[Show abstract][Hide abstract] ABSTRACT: Background:
Agents targeting programmed death-1 receptor (PD-1) and its ligand (PD-L1) are showing promising results in non-small-cell lung cancer (NSCLC). It is unknown whether PD-1/PD-L1 are differently expressed in oncogene-addicted NSCLC.
We analysed a cohort of 125 NSCLC patients, including 56 EGFR mutated, 29 KRAS mutated, 10 ALK translocated and 30 EGFR/KRAS/ALK wild type. PD-L1 and PD-1 expression were assessed by immunohistochemistry. All cases with moderate or strong staining (2+/3+) in >5% of tumour cells were considered as positive.
PD-1 positive (+) was significantly associated with current smoking status (P=0.02) and with the presence of KRAS mutations (P=0.006), whereas PD-L1+ was significantly associated to adenocarcinoma histology (P=0.005) and with presence of EGFR mutations (P=0.001). In patients treated with EGFR tyrosine kinase inhibitors (N=95), sensitivity to gefitinib or erlotinib was higher in PD-L1+ vs PD-L1 negative in terms of the response rate (RR: P=0.01) time to progression (TTP: P<0.0001) and survival (OS: P=0.09), with no difference in PD1+ vs PD-1 negative. In the subset of 54 EGFR mutated patients, TTP was significantly longer in PD-L1+ than in PD-L1 negative (P=0.01).
PD-1 and PD-L1 are differentially expressed in oncogene-addicted NSCLC supporting further investigation of specific checkpoint inhibitors in combination with targeted therapies.
British Journal of Cancer 10/2014; 112(1). DOI:10.1038/bjc.2014.555 · 4.84 Impact Factor
"Disappointingly, corresponding vaccination approaches have so far delivered insufficient effects in the clinic (125). A limiting factor is that non-mutated tumor-antigens may not reflect essential molecular functions required for tumor cell survival promoting the generation of escape variants (126). Furthermore, T cell precursors against this type of antigens are subject to thymus selection and self-tolerance mechanisms thus limiting the number of required high-affinity T cell precursors that are essential for effective antitumoral T cell responses. "
[Show abstract][Hide abstract] ABSTRACT: Oncolytic virotherapy has shown impressive results in preclinical studies and first promising therapeutic outcomes in clinical trials as well. Since viruses are known for a long time as excellent vaccination agents, oncolytic viruses are now designed as novel anticancer agents combining the aspect of lysis-dependent cytoreductive activity with concomitant induction of antitumoral immune responses. Antitumoral immune activation by oncolytic virus infection of tumor tissue comprises both, immediate effects of innate immunity and also adaptive responses for long lasting antitumoral activity, which is regarded as the most prominent challenge in clinical oncology. To date, the complex effects of a viral tumor infection on the tumor microenvironment and the consequences for the tumor-infiltrating immune cell compartment are poorly understood. However, there is more and more evidence that a tumor infection by an oncolytic virus opens up a number of options for further immunomodulating interventions such as systemic chemotherapy, generic immunostimulating strategies, dendritic cell-based vaccines, and antigenic libraries to further support clinical efficacy of oncolytic virotherapy.
Frontiers in Oncology 07/2014; 4:188. DOI:10.3389/fonc.2014.00188
"PD-1 has been shown to inhibit both adaptive and innate immune response when
engagement of its ligands PD-L1 (B7-H1) and PD-L2 (B7-DC), which are expressed by tumor
cells, stromal cells, or both [13,14]. PD-L1 is the primary PD-1 ligand that is up-regulated in solid tumors, where
it can inhibit cytokine production and the cytolytic activity of PD-1+
tumor-infiltrating CD4+ and CD8+ T cells [15,16]. Blockade of PD-1/PD-L1 interaction induces potent antitumor effects in
animal models [14,17,18]; furthermore, recent clinical trials show that monoclonal antibodies (mAbs)
specific for PD-1 and PD-L1 mount an impressive antitumor effect in several types of
solid tumors with complete regression observed in some patients [19-21], demonstrating PD-1/PD-L1 pathway as a highly promising target for cancer
[Show abstract][Hide abstract] ABSTRACT: The coinhibitory receptor Programmed Death-1 (PD-1) inhibits effector functions of activated T cells and prevents autoimmunity, however, cancer hijack this pathway to escape from immune attack. The costimulatory receptor glucocorticoid-induced TNFR related protein (GITR) is up-regulated on activated T cells and increases their proliferation, activation and cytokine production. We hypothesize that concomitant PD-1 blockade and GITR triggering would synergistically improve the effector functions of tumor-infiltrating T cells and increase the antitumor immunity. In present study, we evaluated the antitumor effects and mechanisms of combined PD-1 blockade and GITR triggering in a clinically highly relevant murine ID8 ovarian cancer model.
Mice with 7 days-established peritoneal ID8 ovarian cancer were treated intraperitoneally (i.p.) with either control, anti-PD-1, anti-GITR or anti-PD-1/GITR monoclonal antibody (mAb) and their survival was evaluated; the phenotype and function of tumor-associated immune cells in peritoneal cavity of treated mice was analyzed by flow cytometry, and systemic antigen-specific immune response was evaluated by ELISA and cytotoxicity assay.
Combined anti-PD-1/GITR mAb treatment remarkably inhibited peritoneal ID8 tumor growth with 20% of mice tumor free 90 days after tumor challenge while treatment with either anti-PD-1 or anti-GITR mAb alone exhibited little antitumor effect. The durable antitumor effect was associated with a memory immune response and conferred by CD4+ cells and CD8+ T cells. The treatment of anti-PD-1/GITR mAb increased the frequencies of interferon-gamma-producing effector T cells and decreased immunosuppressive regulatory T cells and myeloid-derived suppressor cells, shifting an immunosuppressive tumor milieu to an immunostimulatory state in peritoneal cavity. In addition, combined treatment of anti-PD-1/GITR mAb mounted an antigen-specific immune response as evidenced by antigen-specific IFN-gamma production and cytolytic activity of spleen cells from treated mice. More importantly, combined treatment of anti-PD-1/GITR mAb and chemotherapeutic drugs (cisplatin or paclitaxel) further increased the antitumor efficacy with 80% of mice obtaining tumor-free long-term survival in murine ID8 ovarian cancer and 4 T1 breast cancer models.
Combined anti-PD-1/GITR mAb treatment induces a potent antitumor immunity, which can be further promoted by chemotherapeutic drugs. A combined strategy of anti-PD-1/GITR mAb plus cisplatin or paclitaxel should be considered translation into clinic.
Journal of Translational Medicine 02/2014; 12(1):36. DOI:10.1186/1479-5876-12-36 · 3.93 Impact Factor
Mark C Dessing, Jesper Kers, Jeffrey Damman, Henri G D Leuvenink, Harry van Goor, Jan-Luuk Hillebrands, Bouke G Hepkema, Harold Snieder, Jacob van den Born, Martin H de Borst, Stephan J L Bakker, Gerjan J Navis, Rutger J Ploeg, Sandrine Florquin, Marc Seelen, Jaklien C Leemans