Medicine (Austin & Northern Health) - Theses
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ItemThe Immunological Tumour Microenvironment in Small Cell Lung Cancer and Pulmonary Neuroendocrine Tumours( 2022-11)Background There is a limited understanding of the immunological tumour microenvironment (TME) in pulmonary neuroendocrine tumours (NETs), including well-differentiated (carcinoid) and small cell lung cancer (SCLC). A fuller understanding of the mechanisms by which these tumours escape immune surveillance is required to build on the success using checkpoint inhibitors in pulmonary NETs. This study presents two retrospective cohorts: one of pulmonary carcinoid tumours, and the second of SCLC examining of the IHC analysis of common checkpoints, their correlation with gene expression, and the impact of both on prognosis. In addition, a smaller group of SCLC patients underwent gene expression profiling (GEP), with clustering studies based on T-cell inflammation signatures and their impact on prognosis. Methods Tissue microarrays from 153 histologically-confirmed pulmonary carcinoids and 101 SCLC specimens were scored for IHC staining of immune checkpoints on tumour alone or TME (combined positive score, CPS). Immune checkpoint expression was analysed for impact on overall survival. A subgroup of 30 patients underwent GEP using the Nanostring nCounter Pan-cancer immune panel. Two IFN-G GEP signatures were examined for supervised clustering and impact on survival. Results In carcinoid tumours PD-L1 >5% was seen in 19/153 (12.4%), but only 3/153 (2.0%) expressed PD-L1 >50%. Expression of PD-L1 >5% was more frequent in atypical carcinoid tumours (6/34; 17.7%) than typical carcinoids (13/119; 10.9%; p 0.39 for significance). No significant tumour expression of PD-L2 and TIM3; LAG3 was expressed at low levels (2/153; 1.3%). Checkpoint expression in TME was low, with PD-L1 CPS >10% in 14/153 (9.1%). No significant prognostic impact was seen with checkpoint expression in well-differentiated tumours. PD-L1 was the most frequently expressed checkpoint in SCLC. PD-L1 >5% was seen in 17/101 (16.8%). PD-L2 in 2/101 (1.9%); TIM3 had 1/101 (1.0%); LAG3 in 1/101 (1.0%). Expression was more frequent in the tumour microenvironment with PD-L1 CPS >10% in 18/101 (17.8%); TIM3 CPS >10% in 50/101 (49.5%); LAG3 CPS >10% in 27/101 (26.3%) and PD-L2 CPS >10% in 2/101 (2.0%). 12/101 (11.9%) had co-expression of PD-L1, TIM3 and LAG3. PD-L1 >5% on tumour was associated with improved median OS, 27.7 months vs 12.9 months (p 0.04), as was LAG3 CPS expression, with median OS 18.0 months vs 11.9 months (p 0.02). The greatest improvement in survival was seen in cases with co-expression of checkpoints, median OS 33.0 months vs 12.5 months (p 0.04). Multivariable analysis of survival showed that these differences became non-significant when accounting for stage. Significant heterogeneity was observed in gene expression. Gene expression by mRNA level did not correlate with protein expression by IHC. Supervised clustering with the 18-gene and 28-gene IFN-G GEP signatures showed significant clustering but no significant association with survival. Conclusion Well-differentiated pulmonary NETs express PD-L1 at low rates in typical carcinoids and moderately low rates in atypical carcinoids. PD-L2, LAG3 and TIM3 were not expressed at significant levels on tumour or in the TME. The prognostic impact of checkpoint expression is unclear due to the excellent survival in carcinoid tumours with conventional therapy. In the SCLC cohort, tumour expression of PD-L1 and LAG3 in the TME were associated with improved survival on univariate analysis. Co-expression of immune checkpoints occurred in 16.7% SCLC and was associated with improved survival. These differences were accounted for by stage on multivariable analysis. The cohort showed clustering with T-cell inflamed/IFN-G GEP but there was no significant impact of T-cell inflammation on survival.
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ItemImproving prognostic and therapeutic precision in high-risk diffuse large B-cell lymphoma( 2022)Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy and follows an aggressive clinical course. Standard chemotherapy including rituximab, cyclophosphamide, vincristine, doxorubicin and prednisolone (R-CHOP) can be expected to cure ~60% of patients, but those who experience relapse after initial disease control, or have lymphoma which is refractory to front-line combination chemotherapy have limited salvage options and often succumb to their disease. Identification of the clinical and biological factors underlying these poor responses to R-CHOP remains imprecise. One of the most devastating events is dissemination into the central nervous system (CNS), which is usually fatal despite dedicated intensive CNS-penetrating chemotherapy regimens. The objectives of this thesis were to examine the clinical, biological and immunological drivers behind DLBCL refractoriness and relapse in general, with a particular focus on a) the pathobiology and outcomes of CNS dissemination, b) the toxicity of CNS-directed therapy. Clinically, patients with secondary CNS lymphoma (SCNSL) have an aggressive clinical course and the optimal treatment is not defined. This thesis demonstrates that the primary cause of death in these patients is the CNS disease, and subsequently the importance of adding cytarabine to high-dose methotrexate to adequately treat the CNS component. The development of CNS disease, either synchronously at diagnosis or in relapse, occurs for largely unknown reasons. Clinical risk scores for determining CNS risk are imprecise and pathobiological data are lacking to develop rational drug combinations. This thesis compared genetic and functional drivers of secondary CNS DLBCL (SCNSL) samples with primary CNS lymphoma (PCNSL) and systemic-only DLBCL. SCNSL carries multiple aberrations in antigen presentation mechanisms (MHC, B2M, CD58, CIITA) in similar numbers to PCNSL and far more than systemic-only DLBCL suggesting that failure of antigen presentation is a possible mechanism of CNS dissemination with potential therapeutic implications. High-dose methotrexate itself carries substantial toxicity, the underlying risk for which has been undefined. This thesis evaluated the modifiable risk factors for toxicity with high-dose methotrexate and documented the most critical were dose and interacting/nephrotoxic drugs, and suggests how these observations can impact practice. Determining the likelihood of relapse or refractoriness to R-CHOP in systemic DLBCL has been an area of expansive research since the original international prognostic index was published in 1993. With rare exception, improved prognostication has not led to changes in therapy. Real-time assessment of disease response to R-CHOP using FDG-PET has been shown to improve prognostication, but this thesis demonstrates that it can also be used to identify early those who will have refractory disease. Specifically, those with a Deauville score of 5 following 2 cycles of R-CHOP, or a change in the maximum standard uptake value (SUVmax) of <66% following 4 cycles of R-CHOP are highly likely to have refractory disease and should be evaluated for alternative salvage or clinical trial. In order to relapse, DLBCL must escape immune surveillance, and a lack of diversity of the T-cell receptor repertoire at diagnosis has been associated with relapse. Work in this thesis assessed the T-cell diversity in paired diagnostic and relapsed tumour samples. It was observed that these tumour microenvironments become increasingly dysfunctional at relapse though further narrowing of the T-cell receptor repertoire and change in dominant clones, highlighting that it is not only clonal evolution that plays a role in relapse but also defunct immune responses. The high-risk DLBCL groups evaluated in this thesis demonstrate substantial clinical and biological heterogeneity. Identifying and managing the highest risk subgroups remains a challenge that requires comprehensive and multi-faceted approaches to overcome.