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Cesar Moran
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MA11 - Immunotherapy in Special Populations and Predictive Markers (ID 135)
- Event: WCLC 2019
- Type: Mini Oral Session
- Track: Immuno-oncology
- Presentations: 1
- Now Available
- Moderators:Frank Griesinger, Lecia Sequist
- Coordinates: 9/09/2019, 14:00 - 15:30, Hilton Head (1978)
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MA11.09 - Increased Frequency of Bystander T Cells in the Lungs Is Associated with Recurrence in Localized Non-Small Cell Lung Cancer (Now Available) (ID 955)
14:00 - 15:30 | Author(s): Cesar Moran
- Abstract
- Presentation
Background
Non-small cell lung cancer (NSCLC) exhibits a high mutational burden. As a result, patients afflicted by this tumor type experience greater responses to immune checkpoint blockade. This is largely due to the ability of T cells to destroy tumor cells on the basis of antigens recognized by their T cell receptor (TCR). However, the lungs are exposed to carcinogens and pathogens which can also trigger a T cell response distinct from cancer. Therefore, a better understanding of the T cell repertoire in the lungs is needed to improve upon the success of current immunotherapies in NSCLC.
Method
We obtained peripheral blood, tumors, and adjacent uninvolved lungs from a cohort of 236 early stage NSCLC patients. Whole exome sequencing, RNA microarray, immunohistochemistry (CD3, CD4, CD8, CD57, CD68, FoxP3, CD45RO, GzmB, PD-1, and PD-L1) and T cell repertoire sequencing were performed in NSCLC patients and lungs from organ donors and COPD patients. Antigen specificity was predicted using the Grouping of Lymphocyte Interactions by Paratope Hotspot (GLIPH) algorithm. Single cell TCR and RNA sequencing as well as sequencing of the virome are underway.
Result
Clonality was associated with CD8 T cells (r=0.31; p=0.0003), GzmB (r=0.29; p=0.001) and IFN-γ (r=0.52; p<0.0001) production as well as with tumor mutational burden (r=0.19; p=0.015), HLA-B (r=0.29; p=0.0005) and β2-m expression (r=0.20; p=0.018). Patients with classical EGFR mutations exhibited lower T cell clonality (p=0.003) even after adjustment for TMB, highlighting the impact of this driver mutation on the T cell response. Surprisingly, clonality was higher in the adjacent uninvolved lung than tumor (p<0.0001), suggesting an active antigenic response outside the tumor. Comparison of the composition of the T cell repertoire between the uninvolved lung and tumor revealed 57% of the top 100 T cells in the tumor were also found in the adjacent normal lung, highlighting certain parallels in the ongoing antigenic responses. Deeper analysis suggested that shared T cells may have been reactive against mutations shared between the normal lung and tumor (r=0.23, p=0.028) or viruses (p<0.0001). Accordingly, patients with a more reactive T cell repertoire outside the tumor (i.e. bystanders) exhibited shorter disease-free survival (p=0.036) suggesting these responses against shared mutations and/or viruses may detract from the anti-tumor T cell response.
Conclusion
Our findings highlight the importance of understanding the specificity of the T cell repertoire in the lungs in patients with NSCLC treated with immunotherapy. As a high proportion of bystander T cells appear to reside in the lungs, their reactivation could contribute to the impaired responses and/or increased toxicity observed in certain patients with NSCLC treated with immunotherapy.
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MS08 - Management of Thymic Carcinoma (ID 71)
- Event: WCLC 2019
- Type: Mini Symposium
- Track: Thymoma/Other Thoracic Malignancies
- Presentations: 1
- Now Available
- Moderators:Enrico Ruffini, Giovannella Palmieri
- Coordinates: 9/09/2019, 14:00 - 15:30, Seoul (2007)
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MS08.05 - Basic Pathological Features (Now Available) (ID 3485)
14:00 - 15:30 | Presenting Author(s): Cesar Moran
- Abstract
- Presentation
Abstract
IASLC WCLC 2019
MS08 – Management of Thymic Carcinoma
Cesar A. Moran, MD
Professor of Pathology
M D Anderson Cancer Center
Houston, TC
USA
Pathologic Features
The basic pathological features of thymic carcinomas are essentially those seeing in other tumors elsewhere and require the presence of conventional features such mitotic activity, cellular and nuclear atypia, and necrosis among others. However, the diagnosis of thymic carcinoma contrary to the diagnosis of carcinomas in other anatomical areas requires a more strict radiological correlation, as thymic carcinoma can show similar histological features as other tumors such lung or head and neck area. Therefore, the clinical information of an anterior mediastinal mass in the absence of tumor elsewhere becomes an important diagnostic tool in the assessment of thymic carcinoma.
The histopathological features of thymic carcinomas are vast and highly heterogeneous. It is possible that such heterogeneity may be due the different cell types that may be encountered in the normal thymus. However, in general terms, thymic carcinomas can be separated into neuroendocrine and non-neuroendocrine carcinomas, and further sub-divided into: 1) low grade and 2) high grade carcinomas (see table 1). Among the neuroendocrine carcinomas, similar spectrum as in other organ systems has been recognized, including: low grade, intermediate grade, and high grade neuroendocrine carcinoma. Some of these tumors may have special association with particular syndromes. Aside from the neuroendocrine carcinomas, the vast majority of thymic carcinomas are of the squamous type, which can show diversity in their growth pattern from well-differentiated keratinizing to the high-grade lymphoepithelioma-like carcinoma and anaplastic/pleomorphic carcinoma. In addition, the tumors may show different cell types and growth patterns that may include: papillary, micropapillary, clear cell, sarcomatoid carcinomas, and micronodular among others. In addition, it is important to highlight the occurrence of salivary gland type carcinomas in the thymus, examples of that include: mucoepidermoid carcinoma, adenoid cystic carcinoma and epithelial-myoepithelial carcinoma. More interesting is the fact that a small subset of thymic carcinomas will belong to the adenocarcinoma type, with similar features as those adenocarcinomas in other organ systems – mainly a malignant glandular proliferation. These tumors may also show variability in their growth pattern and may show a solid glandular proliferation or a predominantly mucinous component. Needless to say, these thymic adenocarcinomas can mimic metastatic disease from other organ systems such as lung or colon. Therefore, a close clinical correlation is also highly suggested before determining site of origin. It is due to this heterogeneity that the diagnosis of primary thymic carcinoma requires more strict clinical-radiological-pathological criteria, as there are no pathognomonic features that can define a thymic carcinoma, mainly in cases in which there is only a small mediastinoscopic biopsy for evaluation.
From the immunohistochemical point of view, thymic carcinomas commonly express keratin, keratin 5/6, p63, p40, CD5. In addition, it is also well known that some neuroendocrine markers such as synaptophysin may be seen positive in otherwise conventional thymic carcinomas. On the other hand, thymic adenocarcinomas may express different immunohistochemical phenotype that may include: keratin 7, keratin 20, CDX-2, and CEA. In cases of neuroendocrine carcinomas the use of neuroendocrine markers including chromogranin, synaptophysin, and CD56 may prove useful. However, the grade of differentiation still can be done on morphological grounds. More recently, it has been identified a poorly differentiated carcinoma the so-called NUT carcinoma that by histology most likely represents a poorly differentiated squamous carcinoma but that shows positive staining using the immunohistochemical stain for NUT and also may show more specific cytogenetic and chromosomal abnormalities. Such diagnosis should be suspected in poorly differentiated carcinomas.
Regarding the prognosis of thymic carcinoma, it has been identified that the presence of lymph node metastasis, regardless of the location of the lymph node, plays an important role in the clinical outcome of these patients. Therefore, thymic carcinomas are best suited for a TNM staging, contrary to the use of the TNM for thymomas.
TABLE 1
Histological Variants of Thymic Carcinoma
Low grade High grade Neuroendocrine
Mucoepidermoid carcinoma lymphoepithelioma-like Low grade (carcinoid)
Basaloid carcinoma P.D. squamous cell Ca Intermediate (atypical carcinoid)
Epithelial-myoepithelial Ca Anaplastic Ca High-grade (Small cell Ca)
Well-diff. Squamous cell Ca Sarcomatoid Ca
Rhabdoid Ca
Hepatoid Ca
Micronodular Ca
Papillary/micropapillary Ca
Clear Cell Ca
NUT carcinoma
Adenocarcinoma
REFERENCES
1.Shimosato Y, Kameya T, Nagai K, Suemasu K. Squamous cell carcinoma of the thymus. Analysis of 8 cases. Am J Surg Pathol 1977; 1:109-121.
2.Snover DC, Levine GD, Rosai J. Thymic carcinoma. Five distinctive histological variants. Am J Surg Pathol 1982; 6:451-470.
3.Suster S, Moran CA. Thymic carcinoma. Spectrum of differentiation and histologic types. Pathology 1998; 30:111-112.
4.Moran CA, Suster S. Thymic carcinoma. Current concepts and histological features. Hematol Oncol Clin N Am 2008; 22:393-407.
5. Suster S, Rosai J. Thymic carcinoma. A clinicopathologic study of 60 cases. Cancer 1991; 67:1025-1032.
6.Weissferdt A, Moran CA. Thymic carcinoma, part I. A clinicopathologic and immunohistochemical study of 65 cases. Am J Clin Pathol 2012; 138: 103-114.
7.Weissferdt A, Moran CA. Thymic carcinoma, part 2. A clinicopathologic correlation of 33 cases with a proposed staging system. Am J Clin Pathol 2012; 138:115-121.
8.Kalhor N, Moran CA. Primary thymic adenocarcinomas: a clinicopathological and immunohistochemical study of 16 cases with emphasis on the morphological spectrum of differentiation. Hum Pathol 2018; 74:73-82.
9.Moran CA, Suster S. Neuroendocrine carcinomas (Carcinoid Tumor) of the thymus. A clinicopathologic analysis of 80 cases. Am J Clin Pathol 2000; 114:100-110.
10. Kalhor N, Moran CA. Mediastinal Pathology, Springer 2019, Chapter 8, pp 237-286.
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P1.04 - Immuno-oncology (ID 164)
- Event: WCLC 2019
- Type: Poster Viewing in the Exhibit Hall
- Track: Immuno-oncology
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2019, 09:45 - 18:00, Exhibit Hall
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P1.04-79 - CD73 Expression in Lung Adenocarcinomas and Immunological and Molecular Associations (ID 2412)
09:45 - 18:00 | Author(s): Cesar Moran
- Abstract
Background
Immune checkpoints inhibitors (ICI), in monotherapy or combination with chemotherapy, are the standard of care for lung adenocarcinoma (ADC) patients. Unfortunately, only a restricted number of patients will respond to ICI. Combination therapies such as CD73 inhibitors, are being studied with the goal to achieve synergic effects. CD73 is a membrane-bound protein with immunosuppressive functions. We previously reported that higher immune cell infiltration was associated mainly to CD73 basolateral (BL) expression, in this abstract, we show the correlation of CD73 expression at luminal (L) and BL membrane of ADC malignant cells (MCs), with annotated clinicopathological characteristics, immune and molecular biomarkers.
Method
CD73 IHC expression (clone D7F9A) was evaluated in 106 archived ADCs from patients that underwent surgical treatment without neoadjuvant therapy between February 1999 and February 2012 at MD Anderson Cancer Center (Houston, Texas, USA). We scored % and H-score of CD73 expression at the luminal (L) and basolateral (BL) membrane, we calculated the Total (T) CD73 as the average of L and BL, and classified ADCs in three groups: ‘T High’ (TH) (upper quartile for all tumors); ‘T Low’ (TL); ‘T Neg’ (TN) (<1%). We correlated T, L and BL expression and the three groups with clinicopathological characteristics, mutational status of KRAS and EGFR, TP53, STK11 and Tumor mutation burden (TMB), and cell densities of CD3, CD8, CD68, CD45RO, FOXP3, and Granzyme B, and PD-L1 expression (clone E1L3N) in MCs.
Result
T CD73 expression was found in 76%; BL in 60% and L in 57%; among ADCs with luminal membrane present (n=72), L CD73 was present in 83%. T+ and L+ expression was more frequent in never smokers (p=0.02 and p=0.003). Also higher frequency of L+ was found in older patients (>65) (p=0.01), tumors with non-solid histology patterns (p<0.001), EGFR mutation (p=0.048), non-mutated p53 (p=0.002), negative PD-L1 (p=0.03), and low TMB (<10 mut/MB) (p=0.001). Higher levels of L expression were found in KRAS mutated tumors (p=0.049). Higher BL expression positively correlated with p53 mutated tumors (p=0.038), PD-L1+ in MCs (p=<0.0001), and higher TMB (p=0.040).
Our group analyses revealed that TH and TN were associated with ADCs from patients with >30 pack-year of smoking history (p=0.04), presence of any-solid histology pattern (p=0.03), p53 mutation (p= 0.005) and higher TMB (p=0.003) compared with TL. TH also had higher frequency of PD-L1+ tumors, and a higher cell density of CD3 (p=0.0001), CD8 (p=0.001), CD68 (p=0.048), CD45RO (p=0.036), FOXP3 (p=0.053), and Granzyme B (p=0.024) compared to TL and TN. TN showed higher frequency of STK11 mutation (p=0.034).
Conclusion
Based on the CD73 expression we defined subsets of lung adenocarcinomas that have distinct histological, molecular and immunological characteristics that may play a role in the response to ICI.
Our characterization could help us to understand patient’s response to ICI, and identify patients that could potentially benefit from combination therapies.
