Immune profiling has been widely used to probe mechanisms of immune escape in cancer and identify novel targets for therapy. Two emerging uses of immune signatures are identification of likely responders to immunotherapy regimens among individuals with cancer or to understand the variable responses seen among subjects with cancer in immunotherapy trials. Here the immune profiles of six murine solid tumor models (CT26, 4T1, MAD109, RENCA, LLC, and B16) were correlated to tumor regression and survival in response to two immunotherapy regimens. Comprehensive profiles for each model were generated using quantitative RT-PCR, immunohistochemistry, and flow cytometry techniques, as well as functional studies of suppressor cell populations (Treg and MDSC), to analyze intratumoral and draining lymphoid tissues. Tumors stratified as highly or poorly immunogenic, with highly immunogenic tumors showing significantly greater presence of T-cell co-stimulatory molecules and immunosuppression in the tumor microenvironment. An absence of tumor-infiltrating CTL and mature DC was seen across all models. Delayed tumor growth and increased survival with suppressor cell inhibition and tumor-targeted chemokine +/− DC vaccine immunotherapy was associated with high tumor immunogenicity in these models. Tumor MHC class I expression correlated with overall tumor immunogenicity level and was a singular marker to predict immunotherapy response with these regimens. By using experimental tumor models as surrogates for human cancers, these studies demonstrate how select features of an immune profile may be utilized to identify patients most likely to respond to immunotherapy regimens.

Purpose: Anaplastic lymphoma kinase (ALK)-negative, T-cell, anaplastic, non-Hodgkin lymphoma (T-ALCL) in patients with textured saline and silicone breast implants is a recently recognized clinical entity for which the etiology and optimal treatment remain unknown.Experimental Design: Using three newly established model cell lines from patient biopsy specimens, designated T-cell breast lymphoma (TLBR)-1 to -3, we characterized the phenotype and function of these tumors to identify mechanisms of cell survival and potential therapeutic targets.Results: Cytogenetics revealed chromosomal atypia with partial or complete trisomy and absence of the NPM-ALK (2;5) translocation. Phenotypic characterization showed strong positivity for CD30, CD71, T-cell CD2/5/7, and antigen presentation (HLA-DR, CD80, CD86) markers, and interleukin (IL)-2 (CD25, CD122) and IL-6 receptors. Studies of these model cell lines showed strong activation of STAT3 signaling, likely related to autocrine production of IL-6 and decreased SHP-1. STAT3 inhibition, directly or by recovery of SHP-1, and cyclophosphamide-Adriamycin-vincristine-prednisone (CHOP) chemotherapy reagents, effectively kill cells of all three TLBR models in vitro and may be pursued as therapies for patients with breast implant-associated T-ALCLs.Conclusions: The TLBR cell lines closely resemble the primary breast implant-associated lymphomas from which they were derived and as such provide valuable preclinical models to study their unique biology.

<p>PDF file, 5811K, Supplemental Table 1. Antibody clones used for flow cytometry, immunocytochemistry, and western blotting studies. Supplemental Table 2. Phenotype analysis of TLBR cell lines by flow cytometry. Supplemental Figure 1. Cytogenetic analyses of TLBR cell lines. Supplemental Figure 2. Immunocytochemistry of TLBR cell lines. Supplemental Figure 3. Sensitivity of TLBR cell lines to 5-aza-2'-deoxycytidine (AZA). Supplemental Figure 4. Notch signaling in TLBR cell lines.</p>

<div>Abstract<p><b>Purpose:</b> Anaplastic lymphoma kinase (ALK)–negative, T-cell, anaplastic, non–Hodgkin lymphoma (T-ALCL) in patients with textured saline and silicone breast implants is a recently recognized clinical entity for which the etiology and optimal treatment remain unknown.</p><p><b>Experimental Design:</b> Using three newly established model cell lines from patient biopsy specimens, designated T-cell breast lymphoma (TLBR)-1 to -3, we characterized the phenotype and function of these tumors to identify mechanisms of cell survival and potential therapeutic targets.</p><p><b>Results:</b> Cytogenetics revealed chromosomal atypia with partial or complete trisomy and absence of the NPM-ALK (2;5) translocation. Phenotypic characterization showed strong positivity for CD30, CD71, T-cell CD2/5/7, and antigen presentation (HLA-DR, CD80, CD86) markers, and interleukin (IL)-2 (CD25, CD122) and IL-6 receptors. Studies of these model cell lines showed strong activation of STAT3 signaling, likely related to autocrine production of IL-6 and decreased SHP-1. STAT3 inhibition, directly or by recovery of SHP-1, and cyclophosphamide–Adriamycin–vincristine–prednisone (CHOP) chemotherapy reagents, effectively kill cells of all three TLBR models <i>in vitro</i> and may be pursued as therapies for patients with breast implant–associated T-ALCLs.</p><p><b>Conclusions:</b> The TLBR cell lines closely resemble the primary breast implant–associated lymphomas from which they were derived and as such provide valuable preclinical models to study their unique biology. <i>Clin Cancer Res; 18(17); 4549–59. ©2012 AACR</i>.</p></div>