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BACKGROUND: Neoadjuvant chemotherapy (NAC) is an integral component of T4 breast cancer (BCa) treatment. We compared response to NAC for T4 BCa in the U.S. and Nigeria to direct future interventions. MATERIALS AND METHODS: Cross-sectional retrospective analysis included all patients with non-metastatic T4 BCa treated from 2010 to 2016 at Memorial Sloan Kettering Cancer Center (New York, New York) and Obafemi Awolowo University Teaching Hospitals Complex (Ile Ife, Nigeria). Pathologic complete response (pCR) and survival were compared and factors contributing to disparities evaluated. RESULTS: Three hundred and eight patients met inclusion criteria: 157 (51%) in the U.S. and 151 (49%) in Nigeria. All U.S. patients received NAC and surgery compared with 93 (62%) Nigerian patients. Fifty-six out of ninety-three (60%) Nigerian patients completed their prescribed course of NAC. In Nigeria, older age and higher socioeconomic status were associated with treatment receipt. Fewer patients in Nigeria had immunohistochemistry performed (100% U.S. vs. 18% Nigeria). Of those with available receptor subtype, 18% (28/157) of U.S. patients were triple negative versus 39% (9/23) of Nigerian patients. Overall pCR was seen in 27% (42/155) of U.S. patients and 5% (4/76) of Nigerian patients. Five-year survival was significantly shorter in Nigeria versus the U.S. (61% vs. 72%). However, among the subset of patients who received multimodality therapy, including NAC and surgery with curative intent, 5-year survival (67% vs. 72%) and 5-year recurrence-free survival (48% vs. 61%) did not significantly differ between countries. CONCLUSION: Addressing health system, socioeconomic, and psychosocial barriers is necessary for administration of complete NAC to improve BCa outcomes in Nigeria. IMPLICATIONS FOR PRACTICE: This cross-sectional retrospective analysis of patients with T4 breast cancer in Nigeria and the U.S. found a significant difference in pathologic complete response to neoadjuvant chemotherapy (5% Nigeria vs. 27% U.S.). Five-year survival was shorter in Nigeria, but in patients receiving multimodality treatment, including neoadjuvant chemotherapy and surgery with curative intent, 5-year overall and recurrence-free survival did not differ between countries. Capacity-building efforts in Nigeria should focus on access to pathology services to direct systemic therapy and promoting receipt of complete chemotherapy to improve outcomes.
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Neoplasias de la Mama , Terapia Neoadyuvante , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante , Estudios Transversales , Femenino , Humanos , Nigeria , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate patient and provider experiences using telemedicine for gynecologic visits among a diverse, low-income population. METHODS: Patients attending telemedicine visits at a resident-run gynecology clinic completed a modified Telemedicine Usability Questionnaire and providers completed a survey addressing satisfaction and barriers for each visit. The Telemedicine Usability Questionnaire included six subscales to assess telemedicine usability with 1-5 Likert-scale responses. Statistical analyses included Chi-square, Fisher's exact, Wilcoxon rank sum, Wilcoxon signed-rank, and two-sample t-test. RESULTS: Of 192 patients enrolled, 157 (82%) completed the surveys (87% video visits, 13% telephone visits). Most patients were ethnic minorities (non-Hispanic White-16%, Hispanic-32%, Black-28%, Asian-10%), median age was 40 years (range 18-69), and 63% reported income under $40,000. The total mean Telemedicine Usability Questionnaire score was 4.3/5. The reliability subscale score (3.72/5) was lower compared to all other subscales (p < 0.001). Older respondents were more likely to find telemedicine unreliable (mean age >44 vs <39, p = 0.02). Without telemedicine, 54% would have traveled ≥1â h to appointments, with 46% spending over $35 on travel, and 27% missing ≥ 1 workday. Patients preferred telemedicine for follow-up rather than initial visits (81% vs 33%, p < 0.01). Among providers, residents felt less adequately trained in telemedicine compared to nurse practitioners and fellows (54% vs 46%, p = 0.039). CONCLUSION: Low-income women utilizing telemedicine for outpatient gynecologic care report positive experiences with improved access to healthcare, cost, and time savings compared to in-person visits. Provider experiences were also positive; however, teaching hospitals must evaluate whether trainee providers feel adequately trained to deliver telemedicine visits.
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Myeloid-Derived Suppressor Cells (MDSC) are immature myeloid cells that are potent inhibitors of immune cell function and which accumulate under conditions of inflammation, especially cancer. MDSC are suggested to promote the growth of cancer by both enhancement of tumor angiogenesis and metastasis and also inhibition of antitumor immune responses. The presence of deficient and/or defective antitumor adaptive and innate immune responses, coincident with accumulation of MDSC in lymphoid organs and tumor parenchyma, supports the notion of a causal relationship. The potent ability of MDSC to inhibit several components and phases of immune response highlights the likelihood that targeting the inhibitory functions of MDSC may maximize the therapeutic potential of antitumor immunotherapy. In order to guide the rational development of immunotherapeutic strategies that incorporate inhibition of MDSC activity and enzymatic functions, thorough understanding of the role of MDSC in antitumor immune responses is required. In this manuscript we review the multifaceted inhibitory functions of MDSC and consider the role of MDSC-induced inhibition of antitumor T cell effector phase. Support for this research is from NIH R01 CA108573.
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Células Progenitoras Mieloides/efectos de los fármacos , Neoplasias/patología , Neoplasias/terapia , Linfocitos T/efectos de los fármacos , Aminoácidos/metabolismo , Animales , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/inmunología , Comunicación Celular/efectos de los fármacos , Comunicación Celular/genética , Comunicación Celular/inmunología , Humanos , Tolerancia Inmunológica , Inmunoterapia , Ratones , Células Progenitoras Mieloides/inmunología , Células Progenitoras Mieloides/patología , Neoplasias/inmunología , Neoplasias/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Linfocitos T/inmunología , Linfocitos T/patología , Escape del TumorRESUMEN
The presence in cancer tissue of Ag-specific, activated tumor infiltrating CD8(+) T cells proves that tumors express Ags capable of eliciting immune response. Therefore, in general, tumor escape from immune-mediated clearance is not attributable to immunological ignorance. However, tumor-infiltrating lymphocytes are defective in effector phase function, demonstrating tumor-induced immune suppression that likely underlies tumor escape. Since exocytosis of lytic granules is dependent upon TCR-mediated signal transduction, it is a reasonable contention that tumors may induce defective signal transduction in tumor infiltrating T cells. In this review, we consider the biochemical basis for antitumor T cell dysfunction, focusing on the role of inhibitory signaling receptors in restricting TCR-mediated signaling in tumor-infiltrating lymphocytes.
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Antígenos de Neoplasias/inmunología , Linfocitos T CD8-positivos/inmunología , Neoplasias/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Transducción de Señal/inmunología , Escape del Tumor/inmunología , Animales , Exocitosis/inmunología , HumanosRESUMEN
The immune response to cancer has been long recognized, including both innate and adaptive responses, showing that the immune system can recognize protein products of genetic and epigenetic changes in transformed cells. The accumulation of antigen-specific T cells within the tumor, the draining lymph node, and the circulation, either in newly diagnosed patients or resultant from experimental immunotherapy, proves that tumors produce antigens and that priming occurs. Unfortunately, just as obviously, tumors grow, implying that anti-tumor immune responses are either not sufficiently vigorous to eliminate the cancer or that anti-tumor immunity is suppressed. Both possibilities are supported by current data. In experimental animal models of cancer and also in patients, systemic immunity is usually not dramatically suppressed, because tumor-bearing animals and patients develop T-cell-dependent immune responses to microbes and to either model antigens or experimental cancer vaccines. However, inhibition of specific anti-tumor immunity is common, and several possible explanations of tolerance to tumor antigens or tumor-induced immunesuppression have been proposed. Inhibition of effective anti-tumor immunity results from the tumor or the host response to tumor growth, inhibiting the activation, differentiation, or function of anti-tumor immune cells. As a consequence, anti-tumor T cells cannot respond productively to developmental, targeting, or activation cues. While able to enhance the number and phenotype of anti-tumor T cells, the modest success of immunotherapy has shown the necessity to attempt to reverse tolerance in anti-tumor T cells, and the vanguard of experimental therapy now focuses on vaccination in combination with blockade of immunosuppressive mechanisms. This review discusses several potential mechanisms by which anti-tumor T cells may be inhibited in function.
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Antígenos de Neoplasias/inmunología , Activación de Linfocitos , Neoplasias/inmunología , Transducción de Señal/inmunología , Linfocitos T/inmunología , Escape del Tumor , Animales , Presentación de Antígeno , Complejo CD3/inmunología , Linfocitos T CD8-positivos/inmunología , Vacunas contra el Cáncer , Citotoxicidad Inmunológica , Epítopos , Humanos , Tolerancia Inmunológica , Inmunoterapia , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Ratones , Células Mieloides/inmunología , Neoplasias/terapia , Linfocitos T/patología , Linfocitos T Reguladores/inmunologíaRESUMEN
Cross-presentation of exogenous proteins on MHC class I complexes contributes to the priming CD8(+) T-cell responses. However, the mechanisms by which antigen-presenting cells transfer internalized proteins to the MHC class I loading pathway are not well understood. Endocytosed proteins often appear to require proteasomal processing and transport into the endoplasmic reticulum, but the intracellular routes involved in cross-presentation remain unclear. Understanding the molecular and cellular basis of cross-presentation will illuminate novel aspects of cell physiology and might lead to improved vaccine design.
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Reactividad Cruzada/inmunología , Endocitosis/inmunología , Retículo Endoplásmico/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Transducción de Señal/inmunología , Animales , Retículo Endoplásmico/metabolismo , HumanosRESUMEN
PURPOSE: Cancer incidence is increasing in sub-Saharan Africa, yet there is little information on the capacity of pathology laboratories in this region. We aimed to assess the current state of pathology services in Nigeria to guide strategies to ensure best practices and improve the quality of surgical specimen handling. METHODS: We developed structured pathology survey to assess tissue handling, sample processing, and immunohistochemistry (IHC) capabilities. The survey was distributed electronically to 22 medical centers in Nigeria that are part of established cancer consortia. Data were collected between September and October 2017. RESULTS: Sixteen of 22 centers completed the survey in full. All 16 institutions had at least one board-certified pathologist and at least one full-time laboratory scientist/technologist. The majority of responding institutions (75%) reported processing fewer than 3,000 samples per year. For sample processing, 38% of institutions reported manual tissue processing and 75% processed biopsies and surgical specimens together. The average tissue fixation time ranged from 5 to more than 72 hours before processing and paraffin embedding. Half of the institutions reported having no quality assurance processes to evaluate hematoxylin and eosin-stained slides, and 25% reported having no written operating procedures. Half of the participating institutions have a facility for routine IHC staining, and among these there was considerable variability in processes and validation procedures. External proficiency testing was not common among surveyed sites (38%). CONCLUSION: Data from 16 Nigerian medical institutions indicate deficiencies in standardization, quality control, and IHC validation that could affect the reliability of pathology results. These findings highlight addressable gaps in pathology services that can ensure accurate diagnosis and follow-up for the growing number of patients with cancer in this region.
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Neoplasias/patología , Estudios Transversales , Femenino , Humanos , Incidencia , Masculino , Nigeria , Encuestas y CuestionariosRESUMEN
Growth of cancer in rodent models and in patients elicits immune responses directed toward various antigens expressed by the transformed cell. Clearly though, as most tumors grow, unmanipulated antitumor immune responses are incapable of eliminating cancer. Over the past approximately 15 years, antitumor immunoglobulin and T cells have been used to identify tumor antigens, which in turn, have served as the basis for therapeutic vaccine trials. However, experimental cancer vaccines, although in some patients result in elimination of large tumor burdens, have a low frequency of long-term cancer remission in most patients, ca. <5%. Therefore, as tumors express antigens that distinguish themselves from nontransformed cells in immunological terms (i.e., elicit immune responses to growth of primary tumor and can target tumor cells in vivo), and tumor vaccines prime unsuccessful antitumor immune responses in patients, it is likely that growth of cancer induces immune tolerance to tumor cells. Although there are several types of T cell tolerance, mature, antigen-specific CD8+ T cells isolated from tumors are lytic-defective, implying that the tumor microenvironment inactivates the antitumor effector phase. The nature of the functional local tolerance to antitumor immune response is the subject of this review.
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Antineoplásicos/inmunología , Tolerancia Inmunológica , Neoplasias/inmunología , Escape del Tumor/inmunología , Animales , Antineoplásicos/uso terapéutico , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Transducción de Señal/inmunología , Linfocitos T/inmunología , Carga Tumoral/inmunologíaRESUMEN
Matrix metalloproteinase-2 (MMP-2) is involved in several physiological mechanisms, including wound healing and tumor progression. We show that MMP-2 directly stimulates dendritic cells (DCs) to both upregulate OX40L on the cell surface and secrete inflammatory cytokines. The mechanism underlying DC activation includes physical association with Toll-like receptor-2 (TLR2), leading to NF-κB activation, OX40L upregulation on DCs, and ensuing TH2 differentiation. Significantly, MMP-2 polarizes T cells toward type 2 responses in vivo, in a TLR2-dependent manner. MMP-2-dependent type 2 polarization may represent a key immune regulatory mechanism for protection against a broad array of disorders, such as inflammatory, infectious, and autoimmune diseases, which can be hijacked by tumors to evade immunity.
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Células Dendríticas/inmunología , Metaloproteinasa 2 de la Matriz/fisiología , Receptor Toll-Like 2/metabolismo , Animales , Células Dendríticas/enzimología , Células HEK293 , Humanos , Lipopolisacáridos/farmacología , Metaloproteinasa 9 de la Matriz/metabolismo , Ratones Endogámicos C57BL , FN-kappa B/metabolismo , Ligando OX40/metabolismo , Unión Proteica , Transducción de Señal , Linfocitos T/enzimología , Linfocitos T/inmunología , Factor de Necrosis Tumoral alfa/fisiologíaRESUMEN
CD8(+) tumor infiltrating T cells (TIL) lack effector-phase functions due to defective proximal TCR-mediated signaling previously shown to result from inactivation of p56(lck) kinase. We identify a novel interacting partner for p56(lck) in nonlytic TIL, Protocadherin-18 ('pcdh18'), and show that pcdh18 is transcribed upon in vitro or in vivo activation of all CD8(+) central memory T cells (CD44(+)CD62L(hi)CD127(+)) coincident with conversion into effector memory cells (CD44(+)CD62L(lo)CD127(+)). Expression of pcdh18 in primary CD8(+) effector cells induces the phenotype of nonlytic TIL: defective proximal TCR signaling, cytokine secretion, and cytolysis, and enhanced AICD. pcdh18 contains a motif (centered at Y842) shared with src kinases (QGQYQP) that is required for the inhibitory phenotype. Thus, pcdh18 is a novel activation marker of CD8(+) memory T cells that can function as an inhibitory signaling receptor and restrict the effector phase.
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Linfocitos T CD8-positivos/metabolismo , Cadherinas/metabolismo , Adenocarcinoma/metabolismo , Animales , Cadherinas/genética , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Línea Celular Tumoral , Supervivencia Celular/genética , Supervivencia Celular/fisiología , Células Cultivadas , Neoplasias del Colon/metabolismo , Masculino , RatonesRESUMEN
CD8(+) tumor-infiltrating lymphocytes (TIL) lack in vivo and in vitro lytic function due to a signaling deficit characterized by failure to flux calcium or activate tyrosine kinase activity upon contact with cognate tumor cells. Although CD3 zeta is phosphorylated by conjugation in vitro with cognate tumor cells, showing that TIL are triggered, PLC gamma-1, LAT, and ZAP70 are not activated and LFA-1 is not affinity-matured, and because p56(lck) is required for LFA-1 activation, this implies that the signaling blockade is very proximal. Here, we show that TIL signaling defects are transient, being reversed upon purification and brief culture in vitro, implying a fast-acting "switch". Biochemical analysis of purified nonlytic TIL shows that contact with tumor cells causes transient activation of p56(lck) ( approximately 10 s) which is rapidly inactivated. In contrast, tumor-induced activation of p56(lck) in lytic TIL is sustained coincident with downstream TCR signaling and lytic function. Shp-1 is robustly active in nonlytic TIL compared with lytic TIL, colocalizes with p56(lck) in nonlytic TIL, and inhibition of Shp-1 activity in lytic TIL in vitro blocks tumor-induced defective TIL cytolysis. Collectively, our data support the notion that contact of nonlytic TIL with tumor cells, and not with tumor-infiltrating myeloid-derived suppressor cells, causes activation of Shp-1 that rapidly dephosphorylates the p56(lck) activation motif (Y394), thus inhibiting effector phase functions.
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Adenocarcinoma/inmunología , Linfocitos T CD8-positivos/metabolismo , Neoplasias del Colon/inmunología , Linfocitos Infiltrantes de Tumor , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal/inmunología , Adenocarcinoma/metabolismo , Adenocarcinoma/patología , Animales , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Cromo/metabolismo , Neoplasias del Colon/metabolismo , Neoplasias del Colon/patología , Citotoxicidad Inmunológica , Citometría de Flujo , Immunoblotting , Inmunoprecipitación , Activación de Linfocitos , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/genética , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/metabolismo , Ratones , Ratones Endogámicos C57BL , Nitritos/metabolismo , Proteína Tirosina Fosfatasa no Receptora Tipo 6/antagonistas & inhibidores , Proteína Tirosina Fosfatasa no Receptora Tipo 6/genética , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , ARN Interferente Pequeño/farmacología , Receptores de Antígenos de Linfocitos T/inmunología , Urea/metabolismoRESUMEN
Lytic granule exocytosis is the major pathway used by CD8+ CTL to kill virally infected and tumor cells. Despite the obvious importance of this pathway in adaptive T cell immunity, the molecular identity of enzymes involved in the regulation of this process is poorly characterized. One signal known to be critical for the regulation of granule exocytosis-mediated cytotoxicity in CD8+ T cells is Ag receptor-induced activation of protein kinase C (PKC). However, it is not known which step of the process is regulated by PKC. In addition, it has not been determined to date which of the PKC family members is required for the regulation of lytic granule exocytosis. By combination of pharmacological inhibitors and use of mice with targeted gene deletions, we show that PKCdelta is required for granule exocytosis-mediated lytic function in mouse CD8+ T cells. Our studies demonstrate that PKCdelta is required for lytic granule exocytosis, but is dispensable for activation, cytokine production, and expression of cytolytic molecules in response to TCR stimulation. Importantly, defective lytic function in PKCdelta-deficient cytotoxic lymphocytes is reversed by ectopic expression of PKCdelta. Finally, we show that PKCdelta is not involved in target cell-induced reorientation of the microtubule-organizing center, but is required for the subsequent exocytosis step, i.e., lytic granule polarization. Thus, our studies identify PKCdelta as a novel and selective regulator of Ag receptor-induced lytic granule polarization in mouse CD8+ T cells.
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Gránulos Citoplasmáticos/ultraestructura , Exocitosis/inmunología , Proteína Quinasa C-delta/fisiología , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Antígenos CD8/análisis , Gránulos Citoplasmáticos/inmunología , Exocitosis/genética , Granzimas/metabolismo , Ratones , Ratones Mutantes , Proteína Quinasa C-delta/antagonistas & inhibidores , Proteína Quinasa C-delta/genética , Receptores de Antígenos de Linfocitos T/agonistas , Eliminación de Secuencia , Linfocitos T Citotóxicos/enzimología , Linfocitos T Citotóxicos/ultraestructuraRESUMEN
CD8(+) tumor-infiltrating lymphocytes (TIL) are defective in cytolysis due to tumor-induced inhibition of proximal TCR-mediated signaling, a defect that is relieved upon purification and brief culture. We show in this study that frequency of conjugation in vitro of nonlytic TIL with tumor cells is low in comparison with their lytic counterparts, and the strength of interaction and duration of conjugation are also reduced. Previous reports show that p56(lck) activation is required for TCR-initiated LFA-1 avidity up-regulation, raising the question: is low LFA-1 avidity the basis of reduced TIL conjugation frequency? When stimulated with phorbol ester, nonlytic TIL bind purified ICAM-1 equivalently as lytic TIL, suggesting that LFA-1 can be activated if proximal TCR signaling is bypassed. However, when treated with phorbol ester, the conjugation frequency of nonlytic TIL does not increase. CD2 and CD8 also mediate T cell adhesion to cognate target cells and are both expressed at lower levels in nonlytic TIL in addition to being excluded from the immune synapse formed upon conjugation. Collectively, these results imply that adhesion defects in nonlytic TIL result from a combination of decreased cell surface levels of adhesion molecules, deficient LFA-1 activation, and the failure to recruit essential adhesion receptors to the membrane contact site formed with cognate target cells.
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Linfocitos T CD8-positivos/patología , Linfocitos Infiltrantes de Tumor/patología , Animales , Linfocitos T CD8-positivos/inmunología , Adhesión Celular/inmunología , Línea Celular Tumoral , Pruebas Inmunológicas de Citotoxicidad , Activación de Linfocitos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
CD8+ tumor-infiltrating lymphocytes (TIL) are severely deficient in cytolysis, a defect that may permit tumor escape from immune-mediated destruction. Because lytic function is dependent upon TCR signaling, we have tested the hypothesis that primary TIL have defective signaling by analysis of the localization and activation status of TIL proteins important in TCR-mediated signaling. Upon conjugate formation with cognate target cells in vitro, TIL do not recruit granzyme B+ granules, the microtubule-organizing center, F-actin, Wiskott-Aldrich syndrome protein, nor proline rich tyrosine kinase-2 to the target cell contact site. In addition, TIL do not flux calcium nor demonstrate proximal tyrosine kinase activity, deficiencies likely to underlie failure to fully activate the lytic machinery. Confocal microscopy and fluorescence resonance energy transfer analyses demonstrate that TIL are triggered by conjugate formation in that the TCR, p56lck, CD3zeta, LFA-1, lipid rafts, ZAP70, and linker for activation of T cells localize at the TIL:tumor cell contact site, and CD43 and CD45 are excluded. However, proximal TCR signaling is blocked upon conjugate formation because the inhibitory motif of p56lck is rapidly phosphorylated (Y505) and COOH-terminal Src kinase is recruited to the contact site, while Src homology 2 domain-containing protein phosphatase 2 is cytoplasmic. Our data support a novel mechanism explaining how tumor-induced inactivation of proximal TCR signaling regulates lytic function of antitumor T cells.