Purpose: Tumor-infiltrating lymphocytes (TIL), in particular CD8þ T cells and CD20 þ B cells, are strongly associated with survival in ovarian cancer and other carcinomas. Although CD8 þ TIL can mediate direct cytolytic activity against tumors, the role of CD20 þ TIL is poorly understood. Here, we investigate the possible contributions of CD20 þ TIL to humoral and cellular tumor immunity.Experimental Design: Tumor and serum specimens were obtained from patients with high-grade serous ovarian cancer. CD8þ and CD20 þ TIL were analyzed by immunohistochemistry and flow cytometry.Immunoglobulin molecules were evaluated by DNA sequencing. Serum autoantibody responses to the tumor antigens p53 and NY-ESO-1 were measured by ELISA.Results: The vast majority of CD20 þ TIL were antigen experienced, as evidenced by class-switching, somatic hypermutation, and oligoclonality, yet they failed to express the canonical memory marker CD27. CD20 þ TIL showed no correlation with serum autoantibodies to p53 or NY-ESO-1. Instead, they colocalized with activated CD8 þ TIL and expressed markers of antigen presentation, including MHC class I, MHC class II, CD40, CD80, and CD86. The presence of both CD20 þ and CD8 þ TIL correlated with increased patient survival compared with CD8 þ TIL alone. Conclusions:In high-grade serous ovarian tumors, CD20 þ TIL have an antigen-experienced but atypical CD27 À memory B-cell phenotype. They are uncoupled from serum autoantibodies, express markers of antigen-presenting cells, and colocalize with CD8 þ T cells. We propose that the association between CD20 þ TIL and patient survival may reflect a supportive role in cytolytic immune responses.
Purpose: Prostate tumors express antigens that are recognized by the immune system in a significant proportion of patients; however, little is known about the effect of standard treatments on tumor-specific immunity. Radiation therapy induces expression of inflammatory and immunestimulatory molecules, and neoadjuvant hormone therapy causes prominent T-cell infiltration of prostate tumors. We therefore hypothesized that radiation therapy and hormone therapy may initiate tumor-specific immune responses. Experimental Design: Pretreatment and posttreatment serum samples from 73 men with nonmetastatic prostate cancer and 50 cancer-free controls were evaluated by Western blotting and SEREX (serological identification of antigens by recombinant cDNA expression cloning) antigen arrays to examine whether autoantibody responses to tumor proteins arose during the course of standard treatment. Results: Western blotting revealed the development of treatment-associated autoantibody responses in patients undergoing neoadjuvant hormone therapy (7 of 24, 29.2%), external beam radiation therapy (4 of 29, 13.8%), and brachytherapy (5 of 20, 25%), compared with 0 of 14 patients undergoing radical prostatectomy and 2 of 36 (5.6%) controls. Responses were seen within 4 to 9 months of initiation of treatment and were equally prevalent across different disease risk groups. Similarly, in the murine Shionogi tumor model, hormone therapy induced tumorassociated autoantibody responses in 5 of 10 animals. In four patients, SEREX immunoscreening of a prostate cancer cDNA expression library identified several antigens recognized by treatmentassociated autoantibodies, including PARP1, ZNF707 + PTMA, CEP78, SDCCAG1, and ODF2. Conclusion: We show for the first time that standard treatments induce antigen-specific immune responses in prostate cancer patients. Thus, immunologic mechanisms may contribute to clinical outcomes after hormone and radiation therapy, an effect that could potentially be exploited as a practical, personalized form of immunotherapy.
All reported mutations in the choroideremia (CHM) gene result in the truncation or complete absence of Rab escort protein 1 (REP1). Molecular analysis was carried out on 57 families diagnosed with CHM. Confirmation of the clinical diagnosis is important as end-stage CHM may be clinically similar to the end stages of other retinal degenerative diseases such as RP. The primary means of confirming the diagnosis of CHM is to sequence all 15 exons. An alternative method involves detection of the REP1 protein, as described in MacDonald et al. [1998]. A monoclonal antibody to REP1 does not detect truncated REP1 by immunoblot analysis, presumably due to instability and subsequent degradation of the truncated protein. This analysis provides relatively fast confirmation of the diagnosis, however, protein samples are not always available and are susceptible to degradation, affecting the accurate interpretation of results. CHM gene mutations were found in 54 of 57 families studied. The majority of mutations (>42%) were transitions and transversions. Complete deletions of the CHM gene and deletion/insertion mutations each accounted for almost 4% of the total, while over 9% had large intragenic and other partial deletions. Almost 28% of the mutations were deletions of fewer than 5 base pairs (bp) and almost 13% were splice site mutations. Despite the fact that mutations are found throughout the gene with no common mutation for the disorder, identical mutations have been characterized in unrelated individuals. The majority of these mutations are C to T transitions, changing an arginine residue (CGA) to a stop codon (TGA). Four of the five CGA codons in the CHM gene are sites of recurring mutations.
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