Haemato-Oncology
John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie in Basic Sciences Endocrine Surgery Rhinology, 2018
Oncogenesis can occur at any stage in the haematopoietic hierarchy (Figure 25.1), resulting in a diverse spectrum of malignancies. Diagnosis is frequently dependant on the demonstration that a population of cells are ‘clonal’, meaning that they are all related to a common ancestor. Clonality can be confirmed by unique patterns of expression of cell surface antigens (immunophenotype), the presence of a shared genetic aberration (cytogenetics, molecular genetics) or by expression of the same immunoreceptor (immunoglobulin/TCR rearrangement studies).14 Whilst the concept that a malignant population consists of many identical cells remains clinically useful there has been increasing evidence in recent years that these cancers are genetically diverse disorders with multiple clones often populating the same patient.15 For example, acute myeloid leukaemia (AML) was shown to consist of 2–5 distinct clones in just over half of patients studied. It is likely that such studies significantly underestimate the number of clones present as current methods can only detect clones of a certain size (> 5–10% of cells).16 The prognostic significance of the clonal structure remains unclear at this time.
The Human Cancer Situation
Samuel C. Morris in Cancer Risk Assessment, 2020
Progression has been described as the gradual emancipation of a clone of somatic cells from the complex controls that regulate its growth (Klein, 1987). In other words, “the process whereby tumors go from bad to worse” (Rous and Beard, 1939). It is a dynamic process, since tumors may become increasingly malignant at different rates, and may even evidence remission. The process seems to involve changes within the cancer and interaction between the cancer and other body processes. Continued promotion may be a part of progression, but is not sufficient in itself. The role of carcinogens is not clear, but initiation-promotion experiments on mouse skin indicate distinct differences among chemicals in their ability to promote the appearence of benign papillomas and the ability to produce cancers. Some strong promoters, which produce multiple papillomas, are not effective in the continuing progression of these to cancers (Barrett and Wiseman, 1987).
Clonality, Growth and Spread of Cancer
Jeremy R. Jass in Understanding Pathology, 2020
Clonality implies that cancer, which may comprise thousands of millions of cells, originates from a single cell. The ability of a single cell to give rise to large numbers of cells is not limited to cancer. Normal tissues include a permanent set of stem cells (see Chapter 16). These are like an ancestor from the past who is continually giving birth to new children, grandchildren and great grandchildren; the descendants will pass away but the ancestor is immortal. A cancer can be traced back to an ‘immortal’ stem cell rather than to a descendant that is committed to a limited lifespan. However, most of the cells in a cancer will have a limited lifespan. In fact when one attempts to grow cells from a cancer in a laboratory, they usually die within a short period. Occasionally one cell may survive to form a ‘cell line’ that can be used for further experiments. Such a cell would be the malignant equivalent of a normal stem cell.
Langerhans-type dendritic cells electroporated with TRP-2 mRNA stimulate cellular immunity against melanoma: Results of a phase I vaccine trial
Published in OncoImmunology, 2018
David J. Chung, Richard D. Carvajal, Michael A. Postow, Sneh Sharma, Katherine B. Pronschinske, Justin A. Shyer, Shahnaz Singh-Kandah, Mark A. Dickson, Sandra P. D'Angelo, Jedd D. Wolchok, James W. Young
Clonality, as defined in Methods, is a composite measure of the abundance (frequency) and diversity (uniqueness) of the TCR-V-β repertoire.21 CD4 and CD8 T cells isolated from PBMCs collected at one month after vaccination underwent next-generation deep sequencing of the TCR-V-β CDR3. Pre- to post-vaccination clonality increased in all cases, except one CD4 and one CD8 pair (different subjects); and clonality was significantly higher in the CD8 (P = 0.0097) but not in the CD4 compartment (P = 0.1084) (Figure 4A). Clonality increased 2.11-fold (range 0.85–3.22) for CD4 T cells and 2.94-fold (range 0.98–9.57) for CD8 T cells (Figure 4B). Subset analysis showed a trend in overall lower fold-increases in clonality in patients who relapsed (CD4: 1.83, CD8: 1.54; n = 3) versus non-relapsed patients (CD4: 2.31, CD8: 3.99; n = 4) (Figure 4C). CD8 T cells showed higher clonal frequencies than CD4 T cells one month after LC vaccines (Figure 4D). The mean frequencies in the top clones of post-vaccine samples were higher in both CD4 and CD8 T cells but did not reach statistical significance due to the small sample size (Figure 4D).
Efficacy of PD-1 blockade therapy and T cell immunity in lung cancer patients
Published in Immunological Medicine, 2020
One more critical factor of somatic mutations as effective neoantigens is clonality. Transformation of a cancer cell is caused by accumulated gene alteration in one somatic cell. The mutations accumulated in the original cancer cell will be clonal mutation shared by all clones of cancer. Meanwhile, during proliferation of cancer cells, they acquire more mutations due to genetic instability. This type of mutation varies among cancer clones and mediates heterogeneity. N. McGranahan et al. [16] demonstrated that sensitivity to PD-1 blockade therapy in NSCLC patients was enhanced in tumors enriched with clonal neoantigens. Interestingly, subclonal neoantigens induced by chemotherapy were rich in certain poor responders. This observation is consistent with cancer immune editing theory. Because the elimination phase is supposed to begin very early when one somatic cell is transformed, T cells that mediate elimination phase likely recognize clonal neoantigens. During the equilibrium phase, the immunogenic cancer clones that possess more mutations are supposed to be preferentially eradicated. Thus, increase in subclonal mutations may reflect attenuation of antitumor T cell immunity. Indeed, melanoma study indicated that tumor mutation burden decreased in patients who responded to nivolumab but increased in PD patients [17].
Polyfunctional tumor-reactive T cells are effectively expanded from non-small cell lung cancers, and correlate with an immune-engaged T cell profile
Published in OncoImmunology, 2019
Rosa De Groot, Marleen M. Van Loenen, Aurélie Guislain, Benoît P. Nicolet, Julian J. Freen-Van Heeren, Onno J.H.M. Verhagen, Michel M. Van Den Heuvel, Jeroen De Jong, Patrick Burger, C.Ellen Van Der Schoot, Robbert M. Spaapen, Derk Amsen, John B. A. G. Haanen, Kim Monkhorst, Koen J. Hartemink, Monika C. Wolkers
We next investigated the phenotypic alterations in T cell composition of the expanded TIL products. TIL expansion resulted in a drop of FOXP3-expressing CD4+ to <0.1% of the CD4 T cells (Supplemental Figure 2A). Furthermore, even though LAG-3 and TIGIT expression increased upon T cell cultures, the expression of PD-1 expression substantially diminished upon T cell expansion (Supplemental Figure 2B). We also interrogated whether and how the T cell clonality altered upon T cell expansion. CDR3 nucleic acid sequence analysis of the TCRβ chain revealed that both CD4+ and CD8+ T cells are in general polyclonal in NSCLC tumor lesions, and that this polyclonality is maintained upon expansion (Figure 1(h)). Furthermore, tumor-derived and expanded CD4+ and CD8+ T cells showed overlapping T cell clones, a feature that was more pronounced in CD8+ T cells (Figure 1(h), Supplemental Figure 3). In conclusion, both CD4+ and CD8+ T cells from NSCLC expanded well with the REP culture conditions, and maintained their polyclonal profile.
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