Purpose Cutaneous squamous cell carcinoma (cSCC) is the most common human cancer with metastatic potential. Despite T cells accumulating around cSCCs, these tumors continue to grow and persist. To investigate reasons for failure of T cells to mount a protective response in cSCC, we focused on regulatory T cells (Tregs) as this suppressive population is well represented among the infiltrating lymphocytes. Experimental Design Flow cytometry was conducted on cSCC lymphocytes and in vitro functional assays were performed using sorted tumoral T cells. Lymphocyte subsets in primary cSCCs were quantified immunohistochemically. Results FOXP3+ Tregs were more frequent in cSCCs than in peripheral blood (p<0.0001, n=86 tumors). Tumoral Tregs suppressed proliferation of tumoral effector CD4+ (p=0.005, n=10 tumors) and CD8+ T cells (p=0.043, n=9 tumors) and inhibited interferon-γ secretion by tumoral effector T cells (p=0.0186, n=11 tumors). The costimulatory molecule OX40 was expressed predominantly on tumoral Tregs (p<0.0001, n=15 tumors) and triggering OX40 with an agonist anti-OX40 antibody overcame the suppression exerted by Tregs, leading to increased tumoral effector CD4+ lymphocyte proliferation (p=0.0098, n=10 tumors). Tregs and OX40+ lymphocytes were more abundant in primary cSCCs which metastasized than in primary cSCCs which had not metastasized (n=48 and n=49 tumors respectively). Conclusions Tregs in cSCCs suppress effector T cell responses and are associated with subsequent metastasis, suggesting a key role for Tregs in cSCC development and progression. OX40 agonism reversed the suppressive effects of Tregs in vitro, suggesting that targeting OX40 could benefit the subset of cSCC patients at high risk of metastasis.

A 34-year-old homosexual man with acquired immune deficiency syndrome developed extraocular muscle deficits, chorioretinitis, and paraplegia without sensory symptoms. EMG showed severe diffuse denervation, but only mildly slowed nerve conduction velocities, in both legs. Meningitis persisted for 6 weeks and was exacerbated prior to the patient's death. Necropsy revealed subpial and subependymal cytomegalovirus (CMV) infection. Histology of ventral roots demonstrated proximal CMV infection and massive fiber loss. In this immunosuppressed patient, CMV caused a severe motor polyradiculopathy by selective destruction of the motor neurons of ventral spinal roots and motor cranial nerves.

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<div>Abstract<p><b>Purpose:</b> Cutaneous squamous cell carcinoma (cSCC) is the most common human cancer with metastatic potential. Despite T cells accumulating around cSCCs, these tumors continue to grow and persist. To investigate reasons for failure of T cells to mount a protective response in cSCC, we focused on regulatory T cells (Tregs) as this suppressive population is well represented among the infiltrating lymphocytes.</p><p><b>Experimental Design:</b> Flow cytometry was conducted on cSCC lymphocytes and <i>in vitro</i> functional assays were performed using sorted tumoral T cells. Lymphocyte subsets in primary cSCCs were quantified immunohistochemically.</p><p><b>Results:</b> FOXP3⁺ Tregs were more frequent in cSCCs than in peripheral blood (<i>P</i> < 0.0001, <i>n</i> = 86 tumors). Tumoral Tregs suppressed proliferation of tumoral effector CD4⁺ (<i>P</i> = 0.005, <i>n</i> = 10 tumors) and CD8⁺ T cells (<i>P</i> = 0.043, <i>n</i> = 9 tumors) and inhibited IFNγ secretion by tumoral effector T cells (<i>P</i> = 0.0186, <i>n</i> = 11 tumors). The costimulatory molecule OX40 was expressed predominantly on tumoral Tregs (<i>P</i> < 0.0001, <i>n</i> = 15 tumors) and triggering OX40 with an agonist anti-OX40 antibody overcame the suppression exerted by Tregs, leading to increased tumoral effector CD4⁺ lymphocyte proliferation (<i>P</i> = 0.0098, <i>n</i> = 10 tumors). Tregs and OX40⁺ lymphocytes were more abundant in primary cSCCs that metastasized than in primary cSCCs that had not metastasized (<i>n</i> = 48 and <i>n</i> = 49 tumors, respectively).</p><p><b>Conclusions:</b> Tregs in cSCCs suppress effector T-cell responses and are associated with subsequent metastasis, suggesting a key role for Tregs in cSCC development and progression. OX40 agonism reversed the suppressive effects of Tregs <i>in vitro</i>, suggesting that targeting OX40 could benefit the subset of cSCC patients at high risk of metastasis. <i>Clin Cancer Res; 22(16); 4236–48. ©2016 AACR</i>.</p></div>

<div>Abstract<p><b>Purpose:</b> Cutaneous squamous cell carcinoma (cSCC) is the most common human cancer with metastatic potential. Despite T cells accumulating around cSCCs, these tumors continue to grow and persist. To investigate reasons for failure of T cells to mount a protective response in cSCC, we focused on regulatory T cells (Tregs) as this suppressive population is well represented among the infiltrating lymphocytes.</p><p><b>Experimental Design:</b> Flow cytometry was conducted on cSCC lymphocytes and <i>in vitro</i> functional assays were performed using sorted tumoral T cells. Lymphocyte subsets in primary cSCCs were quantified immunohistochemically.</p><p><b>Results:</b> FOXP3⁺ Tregs were more frequent in cSCCs than in peripheral blood (<i>P</i> < 0.0001, <i>n</i> = 86 tumors). Tumoral Tregs suppressed proliferation of tumoral effector CD4⁺ (<i>P</i> = 0.005, <i>n</i> = 10 tumors) and CD8⁺ T cells (<i>P</i> = 0.043, <i>n</i> = 9 tumors) and inhibited IFNγ secretion by tumoral effector T cells (<i>P</i> = 0.0186, <i>n</i> = 11 tumors). The costimulatory molecule OX40 was expressed predominantly on tumoral Tregs (<i>P</i> < 0.0001, <i>n</i> = 15 tumors) and triggering OX40 with an agonist anti-OX40 antibody overcame the suppression exerted by Tregs, leading to increased tumoral effector CD4⁺ lymphocyte proliferation (<i>P</i> = 0.0098, <i>n</i> = 10 tumors). Tregs and OX40⁺ lymphocytes were more abundant in primary cSCCs that metastasized than in primary cSCCs that had not metastasized (<i>n</i> = 48 and <i>n</i> = 49 tumors, respectively).</p><p><b>Conclusions:</b> Tregs in cSCCs suppress effector T-cell responses and are associated with subsequent metastasis, suggesting a key role for Tregs in cSCC development and progression. OX40 agonism reversed the suppressive effects of Tregs <i>in vitro</i>, suggesting that targeting OX40 could benefit the subset of cSCC patients at high risk of metastasis. <i>Clin Cancer Res; 22(16); 4236–48. ©2016 AACR</i>.</p></div>