MAST CELL TUMORS IN CHEETAH (ACINONYX JUBATUS): A CASE SERIES.

Mast cell tumors in nondomestic felids are rarely reported and their biological characteristics are not well described. A retrospective review of the pathology records of 52 zoo-housed cheetahs (Acinonyx jubatus) identified five cases of mast cell tumor, involving four closely related individuals. The age at initial presentation varied from 14 mo to 6 yr. Four cases presented as solitary or multiple cutaneous masses that were mostly slow growing, up to 20 mm diameter, and predominantly nonulcerated. The diagnosis was made by fine needle aspiration cytology of a lesion in one case and by excisional biopsy in the others. Histopathologically, the lesions resembled low- to intermediate-grade canine mast cell tumors, with variations in the degree of anisocytosis and anisokaryosis. Surgical excision was incomplete for 80% of the cutaneous lesions, but local recurrence was not observed in any case. One animal with cutaneous lesions subsequently developed fatal visceral mastocytosis involving the spleen, liver, and adrenal gland. There was no evidence of lymph node invasion or paraneoplastic gastrointestinal signs in any of the cases.

Prognostic Indicators and Clinical Outcome in Dogs with Subcutaneous Mast Cell Tumors Treated with Surgery Alone: 43 Cases.

The purpose of this study was to determine if clinical findings, histologic grade, or other histologic features were associated with clinical outcome in dogs with subcutaneous mast cell tumors (MCTs). Medical records of 43 client-owned dogs were retrospectively reviewed, and follow-up information was gathered via phone or follow-up examination. Progression-free survival (PFS), disease-free interval (DFI), and overall survival were calculated. Forty-two and twenty-two dogs, respectively, had grade 2 (Patnaik grading system) or low-grade tumors (two-tier grading system). Median PFS was 1474 days. Median DFI was not reached at >1968 days. Overall median survival time was not reached at >1968 days. In univariate analysis, argyrophilic nucleolar organizer regions (AgNORs), proliferating cell nuclear antigen, and mitotic index were negatively prognostic for PFS whereas Ki-67, proliferating cell nuclear antigen, and microvessel density were negatively prognostic for DFI. In multivariate analysis, AgNORs remained negatively prognostic for PFS. Results suggest that proliferation indices, especially AgNORs, may be useful in predicting the rare poor outcomes in dogs with subcutaneous MCTs. The vast majority of subcutaneous MCTs appear to be low or intermediate grade with excellent outcomes from good local tumor control.

Grading Cutaneous Mast Cell Tumors in Cats.

Cutaneous mast cell tumors (cMCTs) account for approximately 20% of skin neoplasms in cats. As there is no grading system for these tumors, prognosis is difficult to estimate. Although the typical presentation is a benign tumor that can be cured by surgical excision, a small but important proportion of feline cMCTs is biologically aggressive and can spread to local lymph nodes, precede the onset of disseminated cutaneous disease, or be associated with visceral involvement. A number of macroscopic and histologic features were retrospectively evaluated in cases of feline cMCTs treated with surgical excision with or without medical therapy. Cats were divided into 2 groups based on the clinical outcome. Group 1 included cats alive with no mast cell tumor-related disease at 1000 days from surgery; group 2 included cats developing histologically confirmed metastatic or cutaneous disseminated disease. The criteria allowing the best differentiation between the groups were used to develop a grading scheme. Groups 1 and 2 were composed by 48 (76%) and 15 (24%) cases, respectively. Tumors were classified as high grade if there were >5 mitotic figures in 10 fields (400×) and at least 2 of the following criteria: tumor diameter >1.5 cm, irregular nuclear shape, and nucleolar prominence/chromatin clusters. According to this scheme, the 15 (24%) high-grade cMCTs had significantly reduced survival time (median, 349 days; 95% CI, 0-739 days) as compared with the 48 low-grade tumors (median not reached; P < .001). Further studies are warranted to validate this grading system and test reproducibility on a larger case series.

Immunophenotype of pediatric-onset mastocytosis does not correlate with clinical course.

BACKGROUND: Pediatric mastocytosis differs from adult mastocytosis in its presentation and clinical course. However, the data regarding the immunophenotypic characterization of mast cells in children are limited. Our objective was to evaluate the immunophenotype of mast cells in pediatric mastocytosis and correlate it with the clinical course. METHODS: Biopsy specimens of children with cutaneous mastocytosis were retrieved from the institutions of pathology and were stained for CD25, CD2, and CD30. The percentage of mast cells and the staining intensity were correlated with the clinical data. RESULTS: Twenty-five biopsy specimens were included in the study. Patients' average age was 15.4 at presentation and 37.5 months at biopsy performance. Clinical presentations included maculopapular cutaneous mastocytosis in 79% and mastocytoma in 21% of cases. CD25, CD2, and CD30 were positive in 60%, 44%, and 84% of the biopsy specimens, respectively. The staining score was significantly higher for CD30 as compared to those for CD25 and CD2 (P = 0.02). No correlation was found between the immunophenotype and the clinical form or course of disease. CONCLUSIONS: Our results confirm that CD30 is a sensitive marker for pediatric-onset mastocytosis. Nevertheless, its expression does not correlate with clinical subtype or clinical course. The sensitivity of CD25 is higher than that of CD2 in skin lesions.

Nanog Expression and Proliferation Indices in Canine Cutaneous Mast Cell Tumors.

Mast cell tumors are one of the most frequent skin tumors in dogs. Treatment decisions often depend on a wide range of clinical information and the main criteria for prognostic formulation are histological grade, mitotic count, Ki67 index, and KIT immunostaining pattern. NANOG is a pluripotency factor expressed by normal and cancer stem cells, which is a prognostic marker and a potential therapeutic target for several human tumors. In the present study, mast cell tumor samples from 41 dogs were evaluated for NANOG and Ki67 by immunohistochemistry. All samples were positive for NANOG but its expression was not correlated with Ki67 index and no significant differences were found with respect to histopathological grades, disease-related mortality, or survival. Our results suggest that, although related to pluripotency, NANOG expression does not correlate with proliferative activity, and is not a reliable prognostic factor for canine cutaneous mast cell tumors.

Epidemiological Study of Canine Mast Cell Tumours According to the Histological Malignancy Grade.

The aim of the study was to identify significant relationships between the tumour malignancy grade and dogs' age, breed, sex, size, and location of mast cell tumours (MCTs). MCTs accounted for 13.27% of all diagnosed canine skin tumours. The highest incidence was recorded among Boxers, Labrador Retrievers, American Staffordshire Terriers, and Golden Retrievers. Statistical analysis revealed significantly higher probability of occurrence of the grade I mast cell tumour in the French Bulldog in the head, neck, torso, and limb regions, the grade-II mast cell tumour in Boxer, Doberman, Dachshund, shepherds, and setters in the scrotal region, and the grade III mast cell tumour in Shar-Pei in the axilla region. In the group of the oldest dogs aged 11-16, there was higher risk of development of MCTs grade II and III. Young dogs (aged 2-3 and 4-6) were found to be more prone to development of MCTs grade I. There was no correlation between MCTs grade and dogs' sex and size. To the authors' knowledge this is the first report on statistical relationships between the degree of mast cell tumour malignancy and dogs' phenotypic traits, age and tumour location. This analysis indicate predilections for development of the particular mast cell tumour malignancy degrees in certain dog breeds, age, and anatomical location.

Curcumin analogue, A13, exhibits anti-leukemia effect via inhibiting STAT3.

Abnormal activation of signal transducer and activator of transcription 3 (STAT3) was reported in some leukemia, and inhibition of STAT3 can be the strategy for the leukemia treatment in clinic. In this study, we tested the anti-tumor effect of compound A13, a water-soluble analogue of curcumin, in vitro and in vivo. Herein, we show that A13 was able to reduce the viability of mastocytoma (P815 cells) and reticulum cell sarcoma (A20 cells) as measured by MTS assay. This effect was accompanied by a marked increase in the proportion of apoptotic cells as measured by flow cytometry. Furthermore, Western blot analysis suggested that the anti-leukemia effect of A13 was realized via STAT3 inhibition. In addition, systemic treatment with A13 in the A20-bearing mice for 60 days resulted in a significant improvement of survival rate and marked reduction of liver metastasis. In summary, our data show that the A13 treatment could effectively be applied to acute leukemia via inhibiting STAT3 signaling pathway.

MicroRNAs transfer from human macrophages to hepato-carcinoma cells and inhibit proliferation.

Recent research has indicated a new mode of intercellular communication facilitated by the movement of RNA between cells. There is evidence that RNA can transfer between cells in a multitude of ways, including in complex with proteins or lipids or in vesicles, including apoptotic bodies and exosomes. However, there remains little understanding of the function of nucleic acid transfer between human cells. In this article, we report that human macrophages transfer microRNAs (miRNAs) to hepato-carcinoma cells (HCCs) in a manner that required intercellular contact and involved gap junctions. Two specific miRNAs transferred efficiently between these cells--miR-142 and miR-223--and both were endogenously expressed in macrophages and not in HCCs. Transfer of these miRNAs influenced posttranscriptional regulation of proteins in HCCs, including decreased expression of reporter proteins and endogenously expressed stathmin-1 and insulin-like growth factor-1 receptor. Importantly, transfer of miRNAs from macrophages functionally inhibited proliferation of these cancerous cells. Thus, these data led us to propose that intercellular transfer of miRNA from immune cells could serve as a new defense against unwanted cell proliferation or tumor growth.

Mast cell tumor invading the cornea in a horse.

A 3-year-old Marwari mare was presented for evaluation of an irregular, reddish mass protruding from behind the right third eyelid. The mass appeared to arise at the ventral limbal area, involved the perilimbal bulbar conjunctiva and widely extended into corneal tissue. No other ocular or systemic abnormalities were detected at the time of presentation. The mass was surgically removed by lamellar keratectomy, with defocused CO(2) laser used as adjunctive therapy to treat the surgical exposed area and its surroundings. Histopathologic evaluation showed sheets of densely packed, well-differentiated neoplastic mast cells separated by fibrovascular connective tissue. Nuclear staining for Ki-67 was performed, and an average of 370 cells were positive per 1000 counted cells. Two months postoperatively, the surgical site was filled with flat fibrovascular and pigmented tissue, while the surrounding cornea was transparent with no superficial vascularization around the fibrotic scar. Thirty-two months after treatment, no recurrence of the neoplasia was reported.

Histopathological features of subcutaneous and cutaneous mast cell tumors in dogs.

BACKGROUND: Mast cell tumors (MCTs) are the most common malignant skin neoplasms in dogs. In the past, the distinction between cutaneous MCTs (cMCTs), originating from the dermis, and subcutaneous MCTs (scMCTs), originating from the subcutaneous tissue, was not made. Histopathological differentiation, including grading, is important for prognosis. However, the Patnaik and Kiupel grading systems were proposed for cMCTs only. The objective of our study was to describe and compare the signalment of dogs with scMCTs and cMCTs and histopathological features, anticipating similarities in both groups. Data of dogs histologically diagnosed with scMCTs or cMCTs between September 2020 and July 2023 were analyzed retrospectively. Signalment, tumor location, histopathological features, completeness of removal and lymph node status were recorded. RESULTS: Data on 305 scMCTs and 1291 cMCTs were collected. Breed distribution was different between scMCTs and cMCTs (P < 0.0001). Mitotic count (MC) was not different between scMCTs (1.63) and cMCTs (1.58) (P = 0.8490). Compared to cMCTs, scMCTs more often had anisokaryosis, bizarre nuclei and multinucleation. Kiupel high grade was more often assigned to scMCTs (51/292, 17.5%) than cMCTs (154/1291, 11.9%) (P = 0.009). The odds of MCTs being assigned a high grade in scMCT was 1.578 higher than in cMCTs (95% confidence interval [1.116-2.232]). CONCLUSIONS: Histopathological differences between scMCTs and cMCTs were observed. A Kiupel high grade was more often assigned to scMCTs than cMCTs. Whether these histopathological findings correlate with clinical outcome has to be established in additional studies.

Weishaar's classification system for nodal metastasis in sentinel lymph nodes: Clinical outcome in 94 dogs with mast cell tumor.

BACKGROUND: The therapeutic role and prognostic relevance of lymphadenectomy in mast cell tumor (MCT) has historically been evaluated on regional rather than sentinel lymph nodes. HYPOTHESIS/OBJECTIVES: To update information about the association of histological nodal (HN) classes with clinical outcome in dogs with MCT after tumor excision and extirpation of normal-sized sentinel nodes (SLN) guided by radiopharmaceutical. ANIMALS: Ninety-four dogs with histologically-confirmed treatment-naïve MCT (71 cutaneous, 22 subcutaneous and 1 conjunctival MCT) were included if without: distant metastases, lymphadenomegaly, concurrent mixed cutaneous, and subcutaneous MCT. METHODS: This was a monoistitutional cohort study. Tumors characteristics were retrieved and SLNs were classified according to Weishaar's system. Incidence of MCT-related events (local, nodal, distant relapse), de novo MCT or other tumors and death (MCT-related and non-MCT-related), were recorded. Incidence curves were compared among the HN classes. RESULTS: Twenty-seven dogs had HN0, 19 HN1, 37 HN2, and 11 HN3 SLN. Thirteen (2 HN0, 4 HN2, and 7 HN3) received adjuvant chemotherapies. Kiupel high grade, increasing number of SLN and lymphocentrums were associated with higher HN classes. Five dogs died for MCT-related causes: 1 low-grade (HN0) and 1 subcutaneous (HN3) had a local relapse, 2 high-grade had distant relapse (HN3-HN0) and 1 dog developed disease progression from a de novo subcutaneous MCT. No nodal relapse was registered. Fourteen dogs developed de novo MCTs. CONCLUSION/DISCUSSION: Low grade/low-risk MCT with nonpalpable and normal sized SLN have a favorable outcome independently from the HN. Result should be considered strictly related to the successful SLN detection guided pre- and intraoperative by radiopharmaceutical markers.

Mastocytemia associated with a visceral mast cell tumor in a Sumatran tiger (Panthera tigris).

A 6-yr-old male Sumatran tiger (Panthera tigris) with no significant past clinical history was anesthetized for clinical examination after 5 days of lethargy. Clinically, the animal presented with anorexia, pale mucous membranes, and icterus. Hematologic results indicated moderate anemia and severe thrombocytopenia and showed a circulating population of atypical mast cells. The tiger died during anesthesia. On postmortem examination, abdominal hemorrhage associated with marked diffuse hepato-splenomegaly and mesenteric, hepatic, and splenic lymph node hypertrophy were observed. A visceral mast cell tumor was confirmed by histologic examination and toluidine blue staining, with splenic, hepatic, lymphoid, renal, and pulmonary infiltration. Hematologic, postmortem, and histologic findings were consistent with mastocytemia associated with the splenic form of mast cell tumor described in domestic cats.

Mastocytosis in children: a single-center long-term follow-up study.

BACKGROUND: Mastocytosis is a heterogeneous group of rare disorders characterized by the accumulation of clonal mast cells in organs such as the skin and bone marrow. The diagnosis of cutaneous mastocytosis (CM) is based on clinical findings, positive Darier's sign, and histopathology, if necessary. METHODS: Medical records of 86 children with CM diagnosed during a 35-year long period were reviewed. Most patients (93%) developed CM during the first year of life (median age 3 months). Clinical features at presentation and during the follow-up period were analyzed. Baseline serum tryptase level was measured in 28 patients. RESULTS: A total of 85% of patients had maculopapular cutaneous mastocytosis/urticaria pigmentosa (MPCM/UP), 9% had mastocytoma, and 6% had diffuse cutaneous mastocytosis (DCM). Boy to girl ratio was 1.1:1. Fifty-four of 86 patients (63%) were followed from 2 to 37 years (median 13 years). Complete resolution was registered in 14% of mastocytoma cases, 14% of MCPM/UP, and in 25% of DCM patients. After the age of 18, skin lesion persisted in 14% mastocytoma, 7% MCPM/UP, and 25% children with DCM. Atopic dermatitis was diagnosed in 9.6% of patients with MPCM/UP. Three of 28 patients had elevated serum tryptase. Prognosis in all patients was good, and there were no signs of progression to systemic mastocytosis (SM). CONCLUSION: To the best of our knowledge, our results represent the longest single-center follow-up study of childhood-onset CM. We found no complications of massive mast cell degranulation or progression to SM.

Tumor expression of CD200 inhibits IL-10 production by tumor-associated myeloid cells and prevents tumor immune evasion of CTL therapy.

CD200 is a cell-surface glycoprotein that functions through interaction with the CD200 receptor on myeloid lineage cells to regulate myeloid cell functions. Expression of CD200 has been implicated in multiple types of human cancer; however, the impact of tumor expression of CD200 on tumor immunity remains poorly understood. To evaluate this issue, we generated CD200-positive mouse plasmacytoma J558 and mastocytoma P815 cells. We found that established CD200-positive tumors were often completely rejected by adoptively transferred CTL without tumor recurrence; in contrast, CD200-negative tumors were initially rejected by adoptively transferred CTL but the majority of tumors recurred. Tumor expression of CD200 significantly inhibited suppressive activity and IL-10 production by tumor-associated myeloid cells (TAMC), and as a result, more CTL accumulated in the tumor and exhibited a greater capacity to produce IFN-gamma in CD200-positive tumors than in CD200-negative tumors. Neutralization of IL-10 significantly inhibited the suppressor activity of TAMC, and IL-10-deficiency allowed TAMC to kill cancer cells and their antigenic variants, which prevented tumor recurrence during CTL therapy. Thus, tumor expression of CD200 prevents tumor recurrence via inhibiting IL-10 production by TAMC.

Ly49D engagement on T lymphocytes induces TCR-independent activation and CD8 effector functions that control tumor growth.

Recent data showing expression of activating NK receptors (NKR) by conventional T lymphocytes raise the question of their role in the triggering of TCR-independent responses that could be damaging for the host. Transgenic mice expressing the activating receptor Ly49D/DAP12 offer the opportunity to better understand the relevance of ITAM signaling in the biology of T cells. In vitro experiments showed that Ly49D engagement on T lymphocytes by a cognate MHC class I ligand expressed by Chinese hamster ovary (CHO) cells or by specific Ab triggered cellular activation of both CD4 and CD8 populations with modulation of activation markers and cytokine production. The forced expression of the ITAM signaling chain DAP12 is mandatory for Ly49D-transgenic T cell activation. In addition, Ly49D stimulation induced T lymphocyte proliferation, which was much stronger for CD8 T cells. Phenotypic analysis of anti-Ly49D-stimulated CD8 T cells and their ability to produce high levels of IFN-gamma and to kill target cells indicate that Ly49D ligation generates effector cytotoxic CD8 T cells. Ly49D engagement by itself also triggered cytotoxic activity of activated CD8 T cells. Adoptive transfer experiments confirmed that Ly49D-transgenic CD8 T cells are able to control growth of CHO tumor cells or RMA cells transfected with Hm1-C4, the Ly49D ligand normally expressed by CHO. In conclusion, Ly49D engagement on T cells leads to T cell activation and to a full range of TCR-independent effector functions of CD8 T cells.

Proposal of a 2-tier histologic grading system for canine cutaneous mast cell tumors to more accurately predict biological behavior.

Currently, prognostic and therapeutic determinations for canine cutaneous mast cell tumors (MCTs) are primarily based on histologic grade. However, the use of different grading systems by veterinary pathologists and institutional modifications make the prognostic value of histologic grading highly questionable. To evaluate the consistency of microscopic grading among veterinary pathologists and the prognostic significance of the Patnaik grading system, 95 cutaneous MCTs from 95 dogs were graded in a blinded study by 28 veterinary pathologists from 16 institutions. Concordance among veterinary pathologists was 75% for the diagnosis of grade 3 MCTs and less than 64% for the diagnosis of grade 1 and 2 MCTs. To improve concordance among pathologists and to provide better prognostic significance, a 2-tier histologic grading system was devised. The diagnosis of high-grade MCTs is based on the presence of any one of the following criteria: at least 7 mitotic figures in 10 high-power fields (hpf); at least 3 multinucleated (3 or more nuclei) cells in 10 hpf; at least 3 bizarre nuclei in 10 hpf; karyomegaly (ie, nuclear diameters of at least 10% of neoplastic cells vary by at least two-fold). Fields with the highest mitotic activity or with the highest degree of anisokaryosis were selected to assess the different parameters. According to the novel grading system, high-grade MCTs were significantly associated with shorter time to metastasis or new tumor development, and with shorter survival time. The median survival time was less than 4 months for high-grade MCTs but more than 2 years for low-grade MCTs.

Canine subcutaneous mast cell tumor: characterization and prognostic indices.

Histologic grading schemes for canine cutaneous mast cell tumors (MCTs) were not developed for subcutaneous MCTs. Despite this, subcutaneous MCTs are currently categorized by many as grade II or higher. The aim of this investigation was to assess the pathology and clinical outcome for subcutaneous MCTs to provide a more accurate prognosis. Information on clinical outcome for 306 dogs was obtained from veterinarians and correlated with histologic features. Mean and median follow-up was 842 and 891 days, respectively (range, 3-2,305 days). Only 27 (9%) were confirmed as mast cell-related deaths. Metastasis occurred in 13 (4%), and 24 (8%) had local reoccurrence, even though 171 (56%) cases had incomplete surgical margins. Median survival time was not reached, and the estimated 6-month, 1-, 2-, and 5-year survival probabilities were 95%, 93%, 92%, and 86%, respectively. Dogs were euthanized or died as a result of local tumor reoccurrence, additional MCT development distant to the surgical site, or metastasis. Decreased survival time was linked to mitotic index (number of mitotic figures per 10 high-power fields), infiltrative growth pattern, and presence of multinucleation. Both univariable and multivariable analysis showed mitotic index to be strongly predictive of survival, local reoccurrence, and metastasis. The results of the study indicate that the majority of subcutaneous MCTs have a favorable prognosis, with extended survival times and low rates of reoccurrence and metastasis.

¹8F-FDG and ¹¹C-MET positron emission tomography findings of cutaneous mast cell tumor in a dog.

A 12-year-old intact male Maltese dog presented with an inguinal mass. Histopathology revealed a grade III mast cell tumor. Computed tomography demonstrated pulmonary and inguinal nodules and masses. Chemotherapy was performed using a vinblastine/prednisone protocol, and the inguinal mass disappeared 5 weeks later. Use of 2-deoxy-2-[¹8F]fluoro-D-glucose (¹8F-FDG) and (L)-[methyl- ¹¹C]methionine (¹¹C-MET)-positron emission tomography (PET) demonstrated hypermetabolic areas in the lungs and inguinal region one week after initial chemotherapy. The standardized uptake values of ¹8F-FDG were not different between lung and inguinal lesions; however, the inguinal lesion had a higher ¹¹C-MET standardized uptake value than the lung lesions. The hypermetabolic area was still visible on the second ¹8F-FDG-PET scan despite the disappearance of the mass. This is the first report of ¹¹C-MET-PET findings associated with a cutaneous mast cell tumor in a dog.

In situ c-KIT mRNA quantification of canine cutaneous mast cell tumours and its relationship to prognostic factors.

Cutaneous mast cell tumours (MCTs) are the most frequent malignant skin tumours in dogs. Mutations in the c-KIT proto-oncogene are correlated with the pathogenesis and aggressiveness of MCTs. To date, studies have focused on c-KIT mutations and KIT protein localization, with a general lack of mRNA-level analyses. In this study, c-KIT mRNA expression was investigated in canine MCTs by RNA in situ hybridization (RNA-ISH). Furthermore, we evaluated associations between c-KIT mRNA expression and the histological grade, KIT immunohistochemical staining pattern and other clinicopathological parameters. c-KIT mRNA expression was observed in all MCT samples, appearing as clusters of dots in the cytoplasm of neoplastic cells. A significant correlation was detected between c-KIT mRNA expression (quantified according to the H-score and the percentage of positive cells) and the histological grade (determined using two-and three-tier grading systems; P < .05). We also found a significant positive correlation (all P < .05) between c-KIT mRNA expression and the proliferation indices (mitotic index, Ki-67, and Ag67). However, no significant associations with c-KIT expression from RNA-ISH were found with respect to different KIT staining patterns. Overall, these results demonstrate that c-KIT mRNA expression might be an additional tool for measuring the c-KIT status in canine cutaneous MCTs and could serve as a potential prognostic factor. Further studies should evaluate the prognostic significance of c-KIT mRNA expression in a large and uniform cohort of canine MCTs.

Cooperative action of CD8 T lymphocytes and natural killer cells controls tumour growth under conditions of restricted T-cell receptor diversity.

In mice expressing a transgenic T-cell receptor (TCR; TCRP1A) of DBA/2 origin with reactivity towards a cancer-germline antigen P1A, the number of TCRP1A CD8+ T cells in lymphoid organs is lower in DBA/2 than in B10.D2 or B10.D2(x DBA/2)F1 mice. This reduction results from haemopoietic cell autonomous differences in the differentiation of the major histocompatibility complex class I-restricted TCRP1A thymocytes controlled by DBA/2 versus B10.D2-encoded genes. We report here that the lower number of TCRP1A CD8+ T cells in DBA/2 mice correlated with their poor resistance to P1A-expressing mastocytoma solid tumours. Functional potency of CD8+ cytolytic T lymphocytes (CTL) from the above strains was not compromised, but their number after expansion appeared to be influenced by their genetic background. Intriguingly, non-transgenic DBA/ 2 mice resisted P1A+ tumours more efficiently despite poor representation of P1A-specific CTL. This was partly the result of their more heterogeneous TCR repertoire, including reactivity to non-P1A tumour antigens because mice that had rejected a P1A+ tumour became resistant to a P1A) variant of the tumour. Such 'cross-resistance' did not develop in the TCRP1A transgenic mice. Nonetheless, reconstitution of RAGo/o mice with TCRP1A CD8+ T cells, with or without CD4+ T cells, or exclusive representation of TCRP1A CD8+ T cells in RAGo/o TCRP1A transgenic mice efficiently resisted the growth of P1A-expressing tumours. Natural killer cells present at a higher number in RAGo/o mice also contributed to tumour resistance, in part through an NKG2D-dependent mechanism. Hence, in the absence of a polyclonal T-cell repertoire, precursor frequencies of natural killer cells and tumour-specific CTL affect tumour resistance.